Bisoxadiazolidine derivative

ABSTRACT

A bisoxadiazolidine dione derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof, which is useful as an insulin sensitivity-increasing drug, and a pharmaceutical composition thereof. ##STR1## each represents a phenylene group 
     L: 
     (1) an oxygen, 
     (2) a ##STR2## (3) a --S(O) n  --, (4) a --CO--, 
     (5) a ##STR3## (6) an alkylene group or an alkenylene group which may respectively be interrupted with an oxygen atom and/or a sulfur atom.

This application is a 371 of PCT/JP9400696 filed Apr. 26, 1994.

TECHNICAL FIELD

This invention relates to a novel bisoxadiazolidine derivative andpharmaceutically acceptable salts thereof which are useful as medicines,particularly as a hypoglycemic drug (insulin sensitivity-increasingdrug) and to a pharmaceutical composition containing the same.

BACKGROUND ART

Sulfonylurea compounds and biguanide compounds are currently usedclinically as synthetic hypoglycemic drugs for the treatment ofdiabetes. Biguanide compounds, however, are rarely used because itinduces lactic acidosis and their application is therefore restricted.On the other hand, sulfonylurea compounds show secure hypoglycemicaction and hardly generate side effects, but it is necessary to takegreat caution in using them because they sometimes cause hypoglycemia.

In recent years, insulin sensitivity-increasing drugs capable of showinghypoglycemic action by increasing insulin sensitivity in peripheraltissues have been drawing attention as a successor for theaforementioned synthetic hypoglycemic drugs.

Compounds having the insulin sensitivity-increasing action have beensynthesized as disclosed, for example, in International PatentPublication No. 92/03425 pamphlet (1992).

Under such circumstances, the inventors of the present invention havepreviously found that a bisoxa or thiazolidine derivative has excellentinsulin sensitivity-increasing action and have filed a patentapplication [cf. International Patent Publication No. 93/03021 pamphlet(1993)].

DISCLOSURE OF THE INVENTION

The inventors of the present invention conducted intensive studies onsubstances having insulin sensitivity-increasing action and found that abisoxadiazolidine derivative represented by the following generalformula (I) has excellent insulin sensitivity-increasing action, henceresulting in the accomplishment of the present invention.

That is, according to the present invention, there is provided abisoxadiazolidine derivative represented by a general formula (I)##STR4## [symbols in the formula represent the following meanings;##STR5## the same or different from each other and each represents aphenylene group which may be substituted,

L:

(1) an oxygen atom,

(2) a group represented by the formula ##STR6## (3) a group representedby the formula --S(O)_(n) --, (4) a group represented by the formula--CO--,

(5) a group represented by the formula ##STR7## (6) an alkylene group oran alkenylene group which may respectively be interrupted with an oxygenatom and/or a sulfur atom and which may respectively be substituted, or

(7) a group represented by a formula ##STR8## R¹ : a hydrogen atom or alower alkyl group, n: 0, 1 or 2,

R² : a hydrogen atom or a lower alkyl group,

L¹ and L² : the same or different from each other and each represents

(1) an oxygen atom,

(2) a group represented by the formula ##STR9## (R¹ is as defined in theforegoing), (3) a group represented by the formula --S(O)_(n) -- (n isas defined in the foregoing),

(4) a group represented by the formula --CO--,

(5) a group represented by the formula ##STR10## (R² is as defined inthe foregoing), or (6) an alkylene group, an alkenylene group or apyridinediyl group which may respectively be interrupted with an oxygenatom and/or a sulfur atom and which may respectively be substituted, and##STR11## a cycloalkanediyl group, an arylene group or a pyridinediylgroup, which may respectively be substituted],

or a pharmaceutically acceptable salt thereof.

The compound of the present invention is a novel compound whosestructure is entirely different from any prior art compounds havinginsulin sensitivity-increasing action, because it has a unique chemicalstructure as a bis form in which(1,3,4-oxadiazolidine-3,5-dione-2-yl)methyl groups are linked to bothends of a connecting group ##STR12##

The following describes the compound of the present invention in detail.

Unless otherwise noted, the term "lower" as used herein in thedefinition of the general formulae means a straight or branched carbonchain having 1 to 6 carbon atoms.

In consequence, illustrative examples of the "lower alkyl group" includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl,2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl,2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl,1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyland the like.

The term "an alkylene group or an alkenylene group which mayrespectively be interrupted with an oxygen atom and/or a sulfur atom andwhich may respectively be substituted" means all of unsubstitutedalkylene groups, unsubstituted alkenylene groups, substituted alkylenegroups, substituted alkenylene groups, unsubstituted alkylene groupsinterrupted with an oxygen atom and/or a sulfur atom, unsubstitutedalkenylene groups interrupted with an oxygen atom and/or a sulfur atom,substituted alkylene groups interrupted with an oxygen atom and/or asulfur atom and substituted alkenylene groups interrupted with an oxygenatom and/or a sulfur atom, and the term "interrupted with an oxygen atomand/or a sulfur atom" means not only the groups in which an oxygen atomand/or sulfur atom is present between alkylene or alkenylene chains,such as -L³ -X¹ -L⁴ -, -L³ -X¹ -L⁴ -X² -L⁵ - and the like (in theseformulae, X¹ and X² may be the same or different from each other andeach represents an oxygen atom or a sulfur atom, and L³, L⁴ and L⁵ maybe the same or different from one another and each represents analkylene group or an alkenylene group), but also the groups in which anoxygen atom and/or sulfur atom is directly linked to the ##STR13## ring,such as -X¹ -L³ -, -L³ -X¹ -, -X¹ -L³ -X² -L⁴ -, -L³ -X¹ -L⁴ -X² -, -X¹-L³ -X² -L² -X³ - and the like (in these formulae, X¹, X², L³ and L⁴ areas defined above, and X³ may be the same as or different from X¹ and X²and represents an oxygen atom or a sulfur atom).

Preferably, these alkylene and alkenylene groups are straight chaingroups having 1 (2 in the case of alkenylene groups) to 12 carbon atomsor branched-chain groups substituted with a lower alkyl group, andillustrative examples of such alkylene groups include methylene,ethylene, methylmethylene, trimethylene, 1-methylethylene,2-methylethylene, tetramethylene, 1-methyltrimethylene,2-methyltrimethylene, 3-methyltrimethylene, 1-ethylethylene,2-ethylethylene, propylmethylene, isopropylmethylene, pentamethylene, 1,2, 3 or 4-methyltetramethylene, 1, 2 or 3-ethyltrimethylene, 1,1-, 1,2-,1,3-, 2,2-, 2,3- or 3,3-dimethyltrimethylene, hexamethylene, 1, 2, 3, 4or 5-methylpentamethylene, 1, 2, 3 or 4-ethyltetramethylene, 1,1-, 1,2-,1,3-, 1,4-, 2,2-, 2,3-, 2,4-, 3,3-, 3,4- or 4,4-dimethyltetramethylene,heptamethylene, 1, 2, 3, 4, 5 or 6-methylhexamethylene, octamethylene,1, 2, 3, 4, 5, 6 or 7-methylheptamethylene, nonamethylene, 1, 2, 3, 4,5, 6, 7 or 8-methyloctamethylene, decamethylene, 1, 2, 3, 4, 5, 6, 7, 8or 9-methylnonamethylene, undecamethylene, 1, 2, 3, 4, 5, 6, 7, 8, 9 or10-methyldecamethylene, dodecamethylene, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10or 11-methylundecamethylene and the like, and illustrative examples ofalkenylene groups include vinylene, propenylene, 2-propenylene,1-methylvinylene, 2-methylvinylene, butenylene, 2-butenylene,3-butenylene, 1,3-butadienylene, 1-methylpropenylene,1-methyl-2-propenylene, pentenylene, 1-methylbutenylene,1-methyl-2-butenylene, 1-methyl-3-butenylene,1,1-dimethyl-2-propenylene, hexenylene, 2-hexenylene, 3-hexenylene,4-hexenylene, 5-hexenylene, 1,3-hexadienylene, 1,3,5-hexatrienylene,1-methyl-2-pentenylene, 1-methyl-3-pentenylene,1,1-dimethyl-2-butenylene, 1,1-dimethyl-3-butenylene, heptenylene,2-heptenylene, 3-heptenylene, 4-heptenylene, 5-heptenylene,6-heptenylene, 1,1-dimethyl-2-pentenylene, 1,1-dimethyl-3-pentenylene,1,1-dimethyl-4-pentenylene, 2-octenylene, 4-octenylene, 7-octenylene,1,3,5,7-octatetraenylene, 1,1-dimethyl-2-hexenylene,1,1-dimethyl-3-hexenylene, 1,1-dimethyl-5-hexenylene, 2-nonenylene,4-nonenylene, 5-nonenylene, 8-nonenylene, 1,1-dimethyl-2-heptenylene,1,1-dimethyl-3-heptenylene, 1,1-dimethyl-4-heptenylene,1,1-dimethyl-6-heptenylene, 2-decenylene, 5-decenylene, 9-decenylene,1,1-dimethyl-2-octenylene, 1,1-dimethyl-4-octenylene,1,1-dimethyl-7-octenylene, 2-undecenylene, 5-undecenylene,6-undecenylene, 10-undecenylene, 1,1-dimethyl-2-nonenylene,1,1-dimethyl-4-nonenylene, 1,1-dimethyl-5-nonenylene,1,1-dimethyl-8-nonenylene, 2-dodecenylene, 6-dodecenylene,11-dodecenylene, 1,1-dimethyl-2-decenylene, 1,1-dimethyl-5-decenylene,1,1-dimethyl-9-decenylene and the like.

Preferred substituents which may substituted on these alkylene andalkenylene groups are halogen atoms, and illustrative examples of suchhalogen atoms include fluorine, chlorine, bromine, iodine and the like.One or two substituents may be contained.

The term "a cycloalkanediyl group, an arylene group or a pyridinediylgroup which may respectively be substituted" represented by ##STR14##means all of unsubstituted cycloalkanediyl groups, unsubstituted arylenegroups, unsubstituted pyridinediyl groups, substituted cycloalkanediylgroups, substituted arylene groups and substituted pyridinediyl groups,preferred examples of cycloalkanediyl groups including those having 3 to7 carbon atoms, such as cyclobutanediyl, cyclopentanediyl,cyclohexanediyl, cycloheptanediyl and the like, and each of thesecycloalkanediyl groups may have 1 or 2 lower alkyl groups as itspreferred substituents, and such lower alkyl groups include thosedescribed in the foregoing as illustrative examples of lower alkylgroups.

Examples of arylene groups include aromatic carbon ring divalent groupssuch as phenylene, naphthalenediyl, anthracenediyl, phenanthrenediyl andthe like.

Substituents which may be substituted on arylene groups, pyridinediylgroups or the arylene group of ##STR15## are not particularly limited,provided that they are used in the art as substituents of aromaticcarbon rings and pyridine rings, and their preferred examples include ahalogen atom, a lower alkyl group, a halogeno-lower alkyl group, a loweralkoxy group, a cyano group, a nitro group and the like, as well as anamino group or a carbamoyl group which may respectively be substitutedwith a lower alkyl group.

Illustrative examples of the "halogen atom" and "lower alkyl group" arethose defined in the foregoing, and the term "halogeno-lower alkylgroup" means a group in which optional hydrogen atom(s) of theaforementioned lower alkyl group are substituted with 1 or more halogenatoms. When a fluorine atom is used as an example of the halogen atom,illustrative examples of the halogeno-lower alkyl group includefluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,pentafluoroethyl, 3,3,3-trifluoropropyl and the like.

Illustrative examples of the "lower alkoxy group" include methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,pentyloxy (amyloxy), isopentyloxy, tert-pentyloxy, neopentyloxy,2-methylbutoxy, 1,2-dimethylpropoxy, 1-ethylpropoxy, hexyloxy and thelike.

The term "amino group which may be substituted with a lower alkyl group"means unsubstituted amino group and amino groups mono- or di-substitutedwith the aforementioned illustrative lower alkyl groups, andillustrative examples of the lower alkyl-substituted amino group includemono-lower alkyl amino groups such as methylamino, ethylamino,propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino,tert-butylamino, pentyl(amyl)amino, isopentylamino, neopentylamino,tert-pentylamino, hexylamino and the like and symmetric or asymmetricdi-lower alkyl amino groups such as dimethylamino, diethylamino,dipropylamino, diisopropylamino, dibutylamino, diisobutylamino,ethylmethylamino, methylpropylamino and the like.

Also, the term "carbamoyl group which may be substituted with a loweralkyl group" means unsubstituted carbamoyl group and carbamoyl groupsmono- or di-substituted with the aforementioned illustrative lower alkylgroups, and illustrative examples of the lower alkyl-substitutedcarbamoyl group include mono-lower alkyl carbamoyl groups such asN-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl,N-isopropylcarbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl,N-sec-butylcarbamoyl, N-tert-butylcarbamoyl, N-pentylcarbamoyl,N-hexylcarbamoyl and the like and symmetric or asymmetric di-lower alkylcarbamoyl groups such as N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,N,N-dipropylcarbamoyl, N,N-dibutylcarbamoyl, N-ethyl-N-methylcarbamoyl,N-methyl-N-propylcarbamoyl, N-ethyl-N-propylcarbamoyl and the like.

Since the compound (I) of the present invention has acidic proton on itsoxadiazolidine rings, it can form salts with bases. Pharmaceuticallyacceptable salts of the compound (I) are included in the presentinvention, and examples of such salts include salts with inorganic basessuch as alkali metals (e.g., sodium and potassium), alkaline earthmetals (e.g., magnesium and calcium) and trivalent metals (e.g.,aluminum) and with organic bases such as methylamine, ethylamine,dimethylamine, diethylamine, trimethylamine, triethylamine,monoethanolamine, diethanolamine, triethanolamine, cyclohexylamine,lysine, ornithine and the like.

Since the compound of the present invention has an oxadiazolidine dione,tautomers based on the presence thereof exist. Also, since certainsubstituents have double bonds or asymmetric carbon atoms, geometricalisomers and optical isomers exist based on the presence thereof. All ofthese isomers in separated forms and mixtures thereof are included inthe present invention.

In addition, since the compound (I) of the present invention and itssalts are isolated in some cases in the form of hydrates or varioussolvates or as polymorphic substances, the present invention alsoinclude these hydrates, various pharmaceutically acceptable solvatessuch as with ethanol and the like and polymorphic substances.

Particularly preferred examples of the compound of the present inventionare compounds in which the substituents which may be substituted on##STR16## are one or more substituents selected from the groupconsisting of a halogen atom, a lower alkyl group, a halogeno-loweralkyl group, a lower alkoxy group, a cyano group, a nitro group, anamino group, a lower alkyl-substituted amino group, a carbamoyl groupand a lower alkyl-substituted carbamoyl group and the substituents whichmay be substituted on the alkylene group and alkenylene group of L¹ andL² are one or more halogen atoms. More preferred examples are those inwhich ##STR17## may be the same or different from each other and eachrepresents a phenylene group which may be substituted with one or moresubstituents selected from the group consisting of a halogen atom, alower alkyl group and a halogeno-lower alkyl group and L is

1) an alkylene group or an alkenylene group which may respectively beinterrupted with an oxygen atom and/or a sulfur atom and which mayrespectively be substituted with one or more halogen atoms, or

2) a group represented by ##STR18## wherein L¹ and L² are respectivelyan alkylene group or an alkenylene group which may respectively beinterrupted with an oxygen atom and/or a sulfur atom and which mayrespectively be substituted with one or more halogen atoms and ##STR19##is a cycloalkanediyl group, an arylene group or a pyridinediyl groupwhich may respectively be substituted with one or more substituentsselected from the group consisting of a halogen atom, a lower alkylgroup, a halogeno-lower alkyl group, a lower alkoxy group, a cyanogroup, a nitro group, an amino group, a lower alkyl-substituted aminogroup, a carbamoyl group and a lower alkyl-substituted carbamoyl group.

The following illustrates most preferred examples of the compound of thepresent invention.

(1)1,3-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]benzene ora pharmaceutically acceptable salt thereof.

(2)1,4-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]-2-buteneor a pharmaceutically acceptable salt thereof (particularly its (Z)form).

(3) 1,9-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]nonaneor a pharmaceutically acceptable salt thereof.

(Production Method)

The compound of the present invention can be produced by employingvarious synthesis methods making use of the characteristics of its basicstructure or its substituents. The following illustrates typicalexamples of the production method.

First Production Method ##STR20## (In the above formulae, ##STR21## andL are as defined in the foregoing, and Y¹ and Y² may be the same ordifferent from each other and each represents a halogen atom, an alkoxygroup, an aralkyloxy group or an aryloxy group.)

The compound (I) of the present invention is produced by allowing abis(N-carbamoyl-N-hydroxyaminomethyl) derivative represented by thegeneral formula (II) to react with a carbonyl compound represented bythe general formula (III).

In this case, examples of the halogen atom represented by Y¹ and Y² areas defined in the foregoing, and lower alkoxy groups (e.g., methoxy andethoxy) may generally be used as the alkoxy group though notparticularly limited to these lower alkoxy groups. The aryloxy andaralkyloxy groups are not particularly limited, provided that they arearomatic carbon ring-oxy groups or aromatic carbon ring-alkoxy groups,and phenoxy, benzyloxy and the like may generally be used.

It is advantageous to carry out the reaction between the compound (II)with 2 mol or excess mol equivalent of the compound (III), preferably,in the presence of a base such as sodium hydroxide, potassium hydroxideor the like at a temperature of from 0° C. to 150° C. in an inertorganic solvent such as tetrahydrofuran, diethyl ether, diisopropylether, dioxane, dimethoxyethane (monoglyme), bis(2-methoxyethyl) ether(diglyme), methanol, ethanol, Cellosolve (trade name, 2-ethoxyethanol),Methylcellosolve (trade name, 2-methoxyethanol), dimethyl sulfoxide,sulfolane or the like, or a mixture thereof.

In this connection, as shown in the following reaction scheme, thestarting compound (II) can be obtained easily by

1) reducing the corresponding bis(formyl) compound (IV) to obtain abis(hydroxymethyl) compound, halogenizing the product to obtain abis(halogenomethyl) compound, allowing the halogeno compound to reactwith protected hydroxy-urea to obtain a bis(N-protectedhydroxy-N-carbamoylaminomethyl) compound (VI) and then eliminating theprotecting group, or

2) subjecting the corresponding formyl compound (IV) to reductiveamination with hydroxylamine using a reducing agent to obtain abis(hydroxyaminomethyl) compound (VII) and allowing the thus obtainedcompound to react with an alkali metal cyanate in the presence of water.##STR22## (In the above formulae, ##STR23## and L are as defined in theforegoing, Y³ represents a halogen atom, R³ represents an easilyremovable protecting group for the hydroxyl group and M represents analkali metal.)

In this case, the halogen atom and alkali metal are as defined in theforegoing, and examples of the protecting group for the hydroxyl groupinclude those which can be easily eliminated, such as aralkyl groups(e.g., benzyl and p-methoxybenzyl), lower alkyl groups (e.g.,tert-butyl) and acyl groups (e.g., acetyl, trifluoroacetyl, andbenzyloxycarbonyl).

The reaction of each step can be carried out by employing generally usedmethods. For example, the reaction for the production of thebis(halogenomethyl) compound (V) from the bis(formyl) compound (IV) maybe effected preferably in an inert organic solvent such as alcohols(e.g., methanol), ethers (e.g., tetrahydrofuran), or a mixture thereof,by reducing the starting compound using a reducing agent such as sodiumborohydrate or the like which is generally used for the production of--CH₂ OH from --CHO and allowing the reduced product to react with ahalogenation agent such as a hydrogen halide. Also, the reaction for theproduction of the bis[N-(protected hydroxy)-N-carbamoylaminomethyl]compound from the compound (V) may be effected by allowing the compound(V) to react with a protected hydroxyurea in an inert organic solventsuch as dimethylformamide or the like which is generally used in theN-alkylation reaction, preferably in the presence of a base such assodium hydride, potassium carbonate or the like, which is usually usedin the N-alkylation reaction. Elimination of the protecting group,though its varies depending on the type of the protecting group, may beeffected by treating the compound with trifluoroacetic acid or the likeacid which is usually used in the elimination of hydroxyl-protectinggroups or, in the case of a protecting group such as a benzyl group, byreducing it for example by catalytic reduction in the presence of acatalyst such as Pd--C or the like.

The reaction for the production of the bis(hydroxymethyl) compound (VII)from the compound (IV) may be effected by allowing the compound (IV) toreact with hydroxylamine or a salt thereof and reducing the thus formedSchiff's base using a reducing agent (e.g., a borane-pyridine complexand sodium borohydrate), which is usually used in the reductiveamination, in an inert solvent, for example, in an organic solvent suchas alcohols (e.g., methanol and ethanol) or aromatic hydrocarbons (e.g.,benzene, toluene, and xylene), or in water or a mixture solvent thereof,if necessary, in the presence of a catalyst such as sodium acetate,p-toluenesulfonic acid or the like and using an azeotropic dehydrationapparatus or a dehydrating agent, if necessary. The Schiff's base can beapplied to the reduction step without isolation.

The reaction for the production of the compound (II) from the compound(VII) may be effected by allowing the compound (VII) to react with analkali metal cyanate in an inert organic solvent such as alcohols (e.g.,methanol and ethanol), ether (e.g., tetrahydrofuran) or a mixturethereof, if necessary, in the presence of an acid catalyst such ashydrochloric acid or the like.

Taking types, etc. of ##STR24## into consideration, the bis(formyl)compound (IV) may be produced by various methods, for example, byemploying etherification or thioetherification in which thecorresponding halide or sulfonate is allowed to react with phenol orthiophenol in the presence of a base, or by reducing the correspondingbis(nitrile) compound (VIII) using a reducing agent such as diisobutylaluminum hydride or the like. When the bis(tolyl) compound (IX) is usedas a starting material, the bis(halogenomethyl) compound (V) can also beproduced by allowing the starting material to react with a halogenationagent.

Second Production Method ##STR25## (In the above formulae, ##STR26## andL are as defined in the foregoing, Y⁴ represents a halogen atom or analkoxy group, and Y⁵ and Y⁶ may be the same or different from each otherand each represents a halogen atom, an alkoxy group, an aralkyloxy groupor an aryloxy group.)

The compound (I) of the present invention can be produced also by usingthe corresponding bis(hydroxyaminomethyl) compound (VII) as a startingmaterial and allowing it to react with isocyanates (X) represented bythe general formula (X) or N-acyl acid imides (XI).

Illustrative examples of the halogen atom, alkoxy group, aralkyloxygroup and aryloxy group are as defined in the foregoing.

Though it varies depending on the type of the starting compound, it isadvantageous to carry out the reaction of the compound (VII) with 2 molor excess mol equivalent of the compound (X) or (XI) at a coolingtemperature to room temperature in an inert solvent, for example, in anorganic solvent such as tetrahydrofuran, dioxane, ethers (e.g., diethylether), dimethylformamide, dimethyl sulfoxide or the like or a mixturesolvent thereof, if necessary, in the presence of a base such as sodiumhydroxide, potassium hydroxide, trimethylamine, triethylamine or thelike.

Third Production Method ##STR27## (In the above formulae, ##STR28## Land Y⁵ are as defined in the foregoing.)

The compound (I) of the present invention can be produced also bycyclizing the correspondingbis(N-hydroxy-N-acylaminocarbonylaminomethyl) compound (XII) through itstreatment with a base.

The base used in the third production method is also used in thisreaction, and the compound (XII) is an intermediate of the thirdproduction method, because it is produced in the third production methodby allowing the compound (VII) to react with the compound (X) in theabsence of base.

In consequence, the base-treatment reaction is carried out in the samemanner as described in the third production method.

Fourth Production Method

A member of the compound of the present invention in which L, L¹ and/orL² is --SO-- or --SO₂ -- can be produced also by oxidizing thecorresponding compound having --S-- or --SO--.

The oxidation can be carried out by applying generally used methodsadvantageously using oxidizing agent such as organic peracids (e.g.,performic acid, peracetic acid, perbenzoic acid, m-chloroperbenzoicacid, perphthalic acid) or hydrogen peroxide.

Other Production Method

Since the compound of the present invention has ether (thioether),amide, imino and similar structures, it can be produced by employingconventional methods such as the aforementioned etherification,thioetherification, amidation, N-alkylation, reductive amination and thelike.

The compound of the present invention produced in this manner isisolated and purified as a free compound or its salt, hydrate or varioustypes of solvate. Pharmaceutically acceptable salts of the compound (I)of the present invention can be produced by subjecting it to aconventional salt forming reaction.

Isolation and purification are carried out by employing generally usedchemical techniques such as extraction, fractional crystallization,various types of separation chromatography and the like.

Tautomers and geometrical isomers can be separated by selectingappropriate starting material or making use of a difference inphysicochemical property between isomers.

Also, optical isomers can be made into stereochemically pure isomers byselecting an appropriate starting material or by racemic resolution of aracemic compound (for example, a method in which a compound is convertedinto a diastereomer salt with a general optically active base and thensubjected to optical resolution).

INDUSTRIAL APPLICABILITY

Since the compound (I) of the present invention and its salts and thelike have excellent hypoglycemic action based on their insulinsensitivity-increasing action, are low in toxicity and hardly cause sideeffects, they are useful as a drug for the prevention and treatment ofdiabetes, particularly non-insulin-dependent diabetes (type II), andvarious types of diabetic complication and as a drug to be used incombination with insulin.

The excellent hypoglycemic action of the compound of the presentinvention based on its insulin sensitivity-increasing action wasconfirmed by the following test methods.

Hypoglycemic Action

Male kk mice of 4 to 5 w were purchased from CLEA Japan Inc. Theseanimals were separately reared with a high calorie food (CMF,manufactured by Oriental Yeast), and the animals of which the bodyweight was more than 40 g were used in the test.

Measurement of the blood sugar level was carried out by collecting a 10μl portion of blood from a tail vein, removing protein from thecollected sample by its treatment with 100 μl of 0.33N perchloric acid,and after centrifugation, measuring glucose in the resulting supernatantby the glucose oxidase method. Six animals having a blood sugar level ofmore than 200 mg/dl were used as one group in the test.

Each drug was suspended in 0.5% methyl cellulose and orally administereddaily for 4 days. Blood samples were collected before and on the fifthday of the drug administration from the tail vein. Blood sugar level wasdetermined with the aforementioned method.

The hypoglycemic activity was expressed as the blood sugar leveldecreasing ratio to the pre-administration level and statisticallyevaluated as a significant threshold value of p=0.05.

*=p<0.05

**=p<0.01

***=p<0.001

As the result, the compound of the present invention showed excellenthypoglycemic action. For example, the compound of Example 6 showed53%*** of blood sugar level decreasing ratio with a dose of 30 mg/day.In addition, low toxicity of the compound of the present invention hasbeen confirmed by a toxicity test.

A pharmaceutical composition which contains one or more of the compoundrepresented by the general formula (I) and pharmaceutically acceptablesalts thereof as the active ingredient is prepared as various dosageforms such as tablets, powders, fine granules, granules, capsules,pills, solutions, injections, suppositories and the like making use ofgenerally used pharmaceutical carriers, excipients and other additives,and is administered orally or parenterally.

Clinical dose of the compound of the present invention to be used inhuman is optionally decided taking into consideration the symptoms, bodyweight, age, sex and the like of each patient and is generally from 1 to2,000 mg per day per adult for oral administration, and the daily doserecited above may be used once a day or divided into several doses perday. Since the dose varies under various conditions, a dose smaller thanthe above range may exert full effect in some cases.

Tablets, powders, granules and the like are used as the solidcomposition for oral administration use of the present invention. Insuch solid composition, one or more active substances are mixed with atleast one inert diluent such as lactose, mannitol, glucose,hydroxypropylcellulose, fine crystalline cellulose, starch,polyvinylpyrrolidone, magnesium metasilicate aluminate or the like. Inaddition to the inert diluent, the composition may also contain otherinactive additive agents in the usual way, which include a lubricantsuch as magnesium stearate, a disintegrator such as fibrin calciumglycolate, a stabilizer such as lactose and a solubilizing orsolubilization assisting agent such as glutamic acid or aspartic acid.If necessary, tablets or pills may be coated with a gastric or entericfilms such as sucrose, gelatin, hydroxypropylcellulose,hydroxypropylmethylcellulose phthalate or the like.

Examples of the liquid composition for use in oral administrationcontains pharmaceutically acceptable emulsions, solutions, suspensions,syrups, elixirs and the like, which contain generally used inertdiluents such as purified water, ethanol and the like. In addition tothe inert diluent, this composition may also contain a solubilizing orsolubilization assisting agent, auxiliary agents (e.g., a moisteningagent), a suspension, a sweetener, a flavoring agent, an aromatic agent,an antiseptic agent and the like.

Examples of injections for parenteral administration use include asepticaqueous or non-aqueous solutions, suspensions and emulsions. Diluents ofaqueous solutions and suspensions include, for example, distilled waterfor injection use and physiological saline. Examples of diluents for usein the non-aqueous solutions and suspensions include propylene glycol,polyethylene glycol, plant oils (e.g., olive oil), alcohols (e.g.,ethanol) and Polysolvate 80 (trade name). Such compositions may furthercontain additive agents such as a tonicity agent, an antiseptic agent, amoistening agent, an emulsifying agent, a dispersing agent, astabilizing agent (e.g., lactose), a solubilizing or solubilizationassisting agent and the like. These agents are sterilized, for example,by filtration through a bacteria-removing filter, addition of abactericide or irradiation. Alternatively, a sterile solid compositionmay first be produced, which is then dissolved in sterile water or asterile injection solvent prior to its use.

BEST MODE OF CARRYING OUT THE INVENTION

The following examples are provided to describe the present inventionfurther in detail.

Since novel compounds are included in the starting materials, examplesof their production are shown in the following as Reference Examples.

Reference Example 1

1,3-Bis(4-formylphenoxy)benzene (6.36 g) was dissolved in a mixedsolvent of 30 ml methanol and 60 ml tetrahydrofuran to which, withice-cooling, was subsequently added 0.76 g of sodium borohydride. After30 minutes of stirring with ice-cooling, the solution was mixed with 80ml of 1N hydrochloric acid and extracted with ethyl acetate. The extractwas dried over anhydrous magnesium sulfate, and the solvent wasevaporated. The thus obtained residue was dissolved in a 4N hydrogenchloride-1,4-dioxane solution and the solution was stirred for 2 hoursat room temperature. The solvent was evaporated under a reducedpressure, and the residue was subjected to silica gel columnchromatography (hexane:ethyl acetate=9:1) to obtain 6.0 g of1,3-bis[(4-chloromethyl)phenoxy]benzene.

Melting point: 37°-39° C.

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR29##

Reference Example 2

2,7-Bis(4-formylphenoxy)naphthalene (2.24 g, 6.09 mmol) was dissolved ina mixed solvent of methanol (20 ml) and tetrahydrofuran (20 ml) towhich, with ice-cooling, was subsequently added sodium borohydride(0.576 g, 15.2 mmol). After 1 hour of stirring at room temperature, thesolution was mixed with 1N hydrochloric acid (60 ml) and extracted withethyl acetate. The extract was dried over anhydrous magnesium sulfateand then the solvent was evaporated.

The thus obtained residue (1.7 g) was added to a 4N hydrogenchloride-1,4-dioxane solution (20 ml) and the mixture was stirred for 3hours at room temperature. After completion of the reaction, the solventwas evaporated and the resulting powder was washed with water anddiethyl ether and then dried to obtain2,7-bis(4-chloromethylphenoxy)naphthalene (1.41 g, 57%).

Melting point: 95°-97° C.

Mass spectrometry data (m/z): 409 (M⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR30##

The following compounds were obtained in the same manner as described inReference Examples 1 and 2.

Bis[(4-chloromethyl)phenyl]ether;

Bis[(4-chloromethyl)phenyl]methane;

1,4-Bis[(4-chloromethyl)phenoxy]benzene;

1,5-Bis[(4-chloromethyl)phenoxy]pentane;

Trans-1,4-bis[[(4-chloromethyl)phenoxy]methyl]cyclohexane;

Cis-1,3-bis[(4-chloromethyl)phenoxy]cyclohexane;

1,2-Bis[(4-chloromethyl)phenoxy]benzene;

Reference Example 3

Dimethylformamide (150 ml) was added to 21.3 g of 1,9-dibromononane,19.8 g of 4-hydroxybenzaldehyde and 21.7 g of potassium carbonate, andthe mixture was stirred at 90° C. for 1.5 hours. The reaction mixturewas cooled to room temperature and poured into water, and the thusformed precipitate was washed with water and then dried under a reducedpressure to obtain 26.9 g of 1,9-bis(4-formylphenoxy)nonane.

Mass spectrometry data (m/z): 368 (M⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 1.20-1.30 (10H, m), 1.65-1.80 (4H, m), 4.07 (4H, t), 7.11 (4H, d),7.86 (4H, d), 9.86 (2H, s)

The following compounds were obtained in the same manner as described inReference Example 3.

Reference Example 4 (Z)-1,4-Bis(4-formylphenoxy)-2-butene

Mass spectrometry data (m/z): 296 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 4.78 (4H, d), 5.97 (2H, t), 7.02 (4H, d), 7.84 (4H, d), 9.90 (2H, s)

Reference Example 5 1,6-Bis(4-formylphenoxy)hexane

Mass spectrometry data (m/z): 326 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.75-1.55 (4H, m), 1.75-1.85 (4H, m), 4.10 (4H, t), 7.12 (4H, d),7.83 (4H, d), 9.89 (2H, s)

Reference Example 6 1,4-Bis(4-formylphenoxy)butane

Mass spectrometry data (m/z): 299 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.70-1.55 (4H, m), 4.14 (4H, m), 7.00 (4H, d), 7.83 (4H, d), 9.89(2H, s)

Reference Example 7 (E)-1,4-Bis(4-formylphenoxy)-2-butene

Mass spectrometry data (m/z): 297 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 4.68 (4H, dd), 6.11 (2H, m), 7.03 (4H, d), 7.83 (4H, d), 9.89 (2H, s)

Reference Example 8 1,7-Bis(4-formylphenoxy)heptane

Mass spectrometry data (m/z): 340 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.10-2.10 (10H, m), 4.05 (4H, t), 6.98 (4H, d), 7.82 (4H, d), 9.88(2H, s)

Reference Example 9 1,3-Bis[(4-formylphenoxy)methyl]benzene

Mass spectrometry data (m/z): 346 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 5.17 (4H, s), 7.07 (4H, d), 7.30-7.70 (4H, m), 7.74 (4H, d), 9.89(2H, s)

Reference Example 10 1,5-Bis(4-formylphenoxy)-3,3-dimethylpentane

Mass spectrometry data (m/z): 340 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.09 (6H, s), 1.87 (4H, t), 4.16 (4H, t), 6.97 (4H, t), 7.87 (4H, t),9.88 (2H, s)

Reference Example 11 Cis-1,3-bis(4-formylphenoxy)cyclopentane

Mass spectrometry data (m/z): 311 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.70-7.50 (6H, m), 4.90-5.20 (2H, m), 6.98 (4H, d), 7.83 (4H, d),9.89 (2H, s)

Reference Example 12 Trans-1,3-bis(4-formylphenoxy)cyclopentane

Mass spectrometry data (m/z): 311 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 2.10-2.25 (5H, m), 2.51-2.58 (1H, m), 4.88-4.95 (2H, m), 6.97 (4H,d), 8.82 (4H, d), 9.87 (2H, s)

The following compounds were obtained in the same manner as described inReference Example 4.

Reference Example 13 1,8-Bis(4-formylphenoxy)octane

Mass spectrometry data (m/z): 354 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 0.90-2.00 (12H, m), 4.04 (4H, t), 6.99 (4H, d), 7.83 (4H, d), 9.88(2H, s)

Reference Example 14 2,2'-Bis(4-formylphenoxy)ethyl ether

Mass spectrometry data (m/z): 314 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 3.80-4.10 (4H, m), 4.10-4.25 (4H, m), 7.02 (4H, d), 7.85 (4H, d),9.87 (2H, s)

Reference Example 15 1,2-Bis(4-formylphenoxy)ethane

Mass spectrometry data (m/z): 271 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 4.45 (4H, m), 7.06 (4H, d), 7.86 (4H, d), 9.91 (2H, s)

Reference Example 16 1,3-Bis(4-formylphenoxy)propane

Mass spectrometry data (m/z): 285 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 2.34 (2H, quint), 4.27 (4H, t), 7.01 (4H, d), 7.83 (4H, d), 9.88 (2H,s)

Reference Example 17 1,10-Bis(4-formylphenoxy)decane

Mass spectrometry data (m/z): 383 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 0.90-2.00 (16H, m), 4.04 (4H, t), 6.98 (4H, d), 7.82 (4H, d), 9.87(2H, s)

Reference Example 18 1,11-Bis(4-formylphenoxy)undecane

Mass spectrometry data (m/z): 397 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 0.90-2.00 (18H, m), 4.04 (4H, t), 7.00 (4H, d), 7.84 (4H, d), 9.88(2H, s)

Reference Example 19 1,12-Bis(4-formylphenoxy)dodecane

Mass spectrometry data (m/z): 411 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 0.90-2.00 (20H, m), 4.04 (4H, t), 6.98 (4H, d), 7.82 (4H, d), 9.87(2H, s)

Reference Example 201,5-Bis(4-formylphenoxy)-2,2,3,3,4,4-hexafluoropentane

Mass spectrometry data (m/z): 421 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 4.58 (4H, s), 7.08 (4H, d), 7.91 (4H, d), 9.93 (2H, s)

Reference Example 21

p-Fluorobenzaldehyde (7.7 g), 5.9 g of 5-chlororesorcinol and 12.3 g ofanhydrous potassium carbonate were added to 50 ml of dimethyl sulfoxideand stirred for 12 hours at 100° C. After completion of the reaction,100 ml of water and 200 ml of ethyl acetate were added to carry outphase separation. After three times of washing with 50 ml of 10% sodiumchloride aqueous solution and subsequent drying over anhydrous magnesiumsulfate, the solvent was evaporated. The resulting oily material wassubjected to silica gel column chromatography (hexane:ethyl acetate(7:1)) to obtain 3.5 g of 1,3-bis(4-formylphenoxy)-5-chlorobenzene.

Mass spectrometry data (m/z): 352 (M⁺) (GC-MS)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 6.69 (1H, t, phenyl), 6.88 (1H, d, phenyl), 7.14 (4H, d, phenyl),7.90 (4H, d, phenyl), 9.95 (2H, s, --CHO)

Reference Example 22

(a) 3,5-Dihydroxytoluol (3.72 g) and 7.62 g of 4-fluorobenzonitrile weredissolved in 50 ml of dimethyl sulfoxide to which was subsequently added2.52 g of 60% sodium hydride. After 4 hours of stirring at 60° C., icewater and ethyl acetate were added to separate the organic layer. Theorganic layer was washed with 10% potassium carbonate aqueous solutionand dried over anhydrous magnesium sulfate, and then the solvent wasevaporated. The residue was recrystallized from isopropanol to obtain5.5 g of 1,3-bis(4-cyanophenoxy)-5-methylbenzene.

Mass spectrometry data (m/z): 326 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)##STR31##

(b) 1,3-Bis(4-cyanophenoxy)-5-methylbenzene (7.06 g) was dissolved in150 ml of methylene chloride, and 53.1 ml of aluminum diisobutylhydride(1.02M toluene solution) was added dropwise to the solution which wasice-cooled. After 30 minutes of stirring with ice-cooling, 100 ml ofsaturated ammonium chloride aqueous solution and 5% sulfuric acid wereadded thereto and the resulting organic layer was separated. The organiclayer was washed with saturated sodium chloride aqueous solution anddried over anhydrous magnesium sulfate and then the solvent wasevaporated. Diisopropyl ether was added to the resulting residue and thethus formed crystals were collected by filtration to obtain 6.5 g of1,3-bis(4-formylphenoxy)-5-methylbenzene.

Mass spectrometry data (m/z): 332 (M⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR32##

Reference Example 23

(a) 40% Potassium fluoride-alumina (3 g) and 0.4 g of 18-crown-6-etherwere added to 50 ml of acetonitrile solution containing 1.55 g ofresorcinol and 5.34 g of 4-fluoro-3-trifluoromethylbenzonitrile. Afterheating the reaction mixture overnight under reflux, insoluble materialswere separated by filtration, diluted with water and extracted withethyl acetate. The organic layer was washed with water and saturatedsodium chloride aqueous solution and then dried over anhydrous magnesiumsulfate. The solvent was evaporated under a reduced pressure and theresulting residue was recrystallized from hexane-ethyl acetate to obtain2.40 g of 1,3-bis(4-cyano-2-trifluoromethylphenoxy)benzene.

Mass spectrometry data (m/z): 449 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 6.88 (1H, t), 6.98-7.03 (4H, m), 7.51 (1H, t), 7.77 (2H, d), 7.99(2H, d)

(b) 1,3-Bis(4-formyl-2-trifluoromethylphenoxy)benzene was obtained inthe same manner as described in Reference Example 22 (b).

Mass spectrometry data (m/z): 455 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 6.90 (1H, t), 6.99-7.02 (2H, m), 7.07 (2H, d), 7.50 (1H, t), 8.01(2H, d), 8.22 (2H, d), 9.98 (2H, s)

Reference Example 24

(a) Anhydrous trifluoroacetic acid (20 ml) was added to 20 ml ofdichloromethane solution containing 1.53 g of 3-(4-cyanophenoxy)aniline,and the reaction mixture was stirred for 30 minutes at room temperature.The solvent was evaporated under a reduced pressure, and the thusobtained residue was dissolved in 40 ml of 2-butanone. Then, 3.14 g ofmethyl iodide and 2.09 g of potassium carbonate were added thereto. Thereaction mixture was heated for 3 hours under reflux, insolublematerials were separated by filtration, and the solvent was evaporatedunder a reduced pressure. To the thus obtained residue were added 30 mlof methanol, 20 ml of water and 1.10 g of potassium carbonate. Thereaction mixture was heated for 2 hours under reflux, diluted with waterand then extracted with ethyl acetate. The organic layer was washed withsaturated sodium chloride aqueous solution and then dried over anhydrousmagnesium sulfate. The solvent was evaporated under a reduced pressure,and the resulting residue was purified by silica gel columnchromatography (eluant; hexane:ethyl acetate=2:1) to obtain 1.52 g of3-(4-cyanophenoxy)-N-methylaniline.

Mass spectrometry data (m/z): 224 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 2.82 (3H, s), 3.86 (1H, s), 6.29 (1H, t), 6.36 (1H, d), 6.46 (1H, d),7.02 (2H, d), 7.18 (1H, t), 7.58 (2H, d)

(b) The following compound was obtained in the same manner as describedin Reference Example 22 (a).

3-(4-Cyanophenoxy)-N-(4-cyanophenyl)-N-methylaniline

Starting compound: 3-(4-cyanophenoxy)-N-methylaniline

Mass spectrometry data (m/z): 325 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 3.37 (3H, s), 6.83-6.91 (4H, m), 7.04-7.06 (3H, m), 7.42 (1H, t),7.47 (2H, d), 7.63 (2H, d)

(c) The following compound was obtained in the same manner as describedin Reference Example 22 (b).

3-(4-Formylphenoxy)-N-(4-formylphenyl)-N-methylaniline

Starting compound: 3-(4-cyanophenoxy)-N-(4-cyanophenyl)-N-methylaniline

Mass spectrometry data (m/z): 331 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 3.41 (3H, s), 6.88-6.97 (4H, m), 7.07-7.12 (3H, m), 7.44 (1H, t),7.72 (2H, d), 7.86 (2H, d), 9.79 (1H, s), 9.94 (1H, s)

Reference Example 25

(a) The following compound was obtained in the same manner as describedin Reference Example 23 (a).

1,3-Bis(4-cyano-2,6-difluorophenoxy)benzene

Mass spectrometry data (m/z): 385 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 6.78-6.81 (2H, m), 6.95 (1H, t), 7.35 (1H, t), 8.07 (4H, d)

(b) The following compound was obtained in the same manner as describedin Reference Example 22 (b).

1,3-Bis(4-formyl-2,6-difluorophenoxy)benzene

Mass spectrometry data (m/z): 391 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 6.64-6.71 (3H, m), 7.24 (1H, t), 7.57 (4H, d), 9.93 (2H, s)

Reference Example 26

(a) The following compound was obtained in the same manner as describedin Reference Example 23 (a).

1,3-Bis(4-cyano-3-trifluoromethylphenoxy)benzene

Mass spectrometry data (m/z): 449 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 7.16-7.20 (3H, m), 7.44-7.47 (2H, m), 7.60-7.64 (3H, m), 8.16 (2H, d)

(b) The following compound was obtained in the same manner as describedin Reference Example 22 (b).

1,3-Bis(4-formyl-3-trifluorophenoxy)benzene

Mass spectrometry data (m/z): 455 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 6.85 (1H, t), 6.98-7.01 (2H, m), 7.22-7.27 (2H, m), 7.37 (2H, d),7.51 (1H, t), 8.14 (2H, d), 10.30 (2H, s)

The following compounds were obtained in the same manner as described inReference Example 3.

Reference Example 27 1,3-Bis(4-formylphenoxy)-4-nitrobenzene

Mass spectrometry data (m/z): 363 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 6.8-7.3 (6H, m), 7.8-8.0 (4H, m), 8.14 (1H, d), 9.95 (1H, s), 9.98(1H, s)

Reference Example 28 2,6-Bis(4-formylphenoxy)benzonitrile

Mass spectrometry data (m/z): 342 ([M-H]⁻)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 6.81 (2H, d), 7.25 (4H, d), 7.52 (1H, t), 7.96 (4H, d), 10.00 (2H, s)

Reference Example 29 2,4-Bis(4-formylphenoxy)benzonitrile

Mass spectrometry data (m/z): 343 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 6.72 (1H, d), 6.89 (2H, dd), 7.19 (2H, d), 7.21 (2H, d), 7.71 (1H,d), 7.94 (4H, d), 9.96 (2H, s)

Reference Example 30

(a) The following compound was obtained in the same manner as describedin Reference Example 22 (a).

1,3-Bis(4-cyanophenoxy)-5-methoxybenzene

Mass spectrometry data (m/z): 342 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 3.78 (3H, s), 6.34 (1H, t), 6.45 (2H, d), 7.06 (4H, d), 7.63 (4H, d)

(b) The following compound was obtained in the same manner as describedin Reference Example 22 (b).

1,3-Bis(4-formylphenoxy)-5-methoxybenzene

Mass spectrometry data (m/z): 348 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 3.78 (3H, s), 6.39 (1H, t), 6.48 (2H, d), 7.13 (4H, d), 7.87 (4H, d),9.94 (2H, s)

Reference Example 31

(a) The following compound was obtained in the same manner as describedin Reference Example 22 (a).

1,3-Bis(4-cyanophenoxy)-5-fluorobenzene

Mass spectrometry data (m/z): 330 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 6.54 (2H, m), 6.65 (1H, d), 7.10 (4H, d), 7.67 (4H, d)

(b) The following compound was obtained in the same manner as describedin Reference Example 22 (b).

1,3-Bis(4-formylphenoxy)-5-fluorobenzene

Mass spectrometry data (m/z): 337 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 6.57 (2H, m), 6.67 (1H, d), 7.16 (4H, d), 7.91 (4H, d), 9.96 (2H, s)

Reference Example 32

(a) The following compound was obtained in the same manner as describedin Reference Example 22 (a).

1,3-Bis(4-cyanophenoxy)-4-bromobenzene

Mass spectrometry data (m/z): 392 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 6.8-7.4 (6H, m), 7.6-7.7 (5H, m)

(b) The following compound was obtained in the same manner as describedin Reference Example 22 (b).

1,3-Bis(4-formylphenoxy)-4-bromobenzene

Mass spectrometry data (m/z): 396 ([M-H]⁻)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 6.8-7.0 (2H, m), 7.0-7.3 (4H, m), 7.68 (1H, d), 7.8-8.0 (4H, m), 9.94(2H, s)

Reference Example 33

(a) The following compound was obtained in the same manner as describedin Reference Example 22 (a).

3,5-Bis(4-cyanophenoxy)-N,N-dimethylaniline

Mass spectrometry data (m/z): 355 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 2.94 (3H, s), 6.05 (1H, t), 6.23 (2H, d), 7.04 (4H, d), 7.60 (4H, d)

(b) The following compound was obtained in the same manner as describedin Reference Example 22 (b).

3,5-Bis(4-formylphenoxy)-N,N-dimethylaniline

Mass spectrometry data (m/z): 361 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 2.95 (3H, s), 6.11 (1H, t), 6.27 (2H, d), 7.10 (4H, d), 7.84 (4H, d),9.92 (2H, s)

Reference Example 34

(a) The following compound was obtained in the same manner as describedin Reference Example 22 (a).

1,3-Bis(4-cyanophenoxy)-4-chlorobenzene

Mass spectrometry data (m/z): 346 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 6.8-7.2 (6H, m), 7.6-7.8 (5H, m)

(b) The following compound was obtained in the same manner as describedin Reference Example 22 (b).

1,3-Bis(4-formylphenoxy)-4-chlorobenzene

Mass spectrometry data (m/z): 352 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 6.9-7.2 (6H, m), 7.52 (1H, d), 7.8-8.0 (4H, m), 9.94 (2H, s)

Reference Example 35

The following compound was obtained by the same treatment as describedin Reference Example 22 (a), followed by the same treatment of ReferenceExample 22 (b) without isolating1,3-bis(4-cyano-2-fluorophenoxy)benzene.

1,3-Bis(2-fluoro-4-formylphenoxy)benzene

Mass spectrometry data (m/z): 354 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 6.8-6.95 (3H, m), 7.10 (2H, d), 7.39 (1H, t), 7.6-7.8 (4H, d), 9.92(2H, d)

Reference Example 36

(a) The following compound was obtained in the same manner as describedin Reference Example 22 (a).

1,3-Bis(2-chloro-4-cyanophenoxy)benzene

Mass spectrometry data (m/z): 381 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 6.72-6.91 (3H, m), 6.99 (2H, d), 7.5 (1H, m), 7.52 (2H, dd), 7.77(2H, d)

(b) The following compound was obtained in the same manner as describedin Reference Example 22 (b).

1,3-Bis(2-chloro-4-formylphenoxy)benzene

Mass spectrometry data (m/z): 387 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 6.78 (1H, t), 6.90 (2H, dd), 7.06 (2H, d), 7.43 (1H, t), 7.74 (2H,dd), 7.99 (2H, d), 9.91 (2H, s)

Reference Example 37

(a) The following compound was obtained in the same manner as describedin Reference Example 22 (a).

1,3-Bis(3-chloro-4-cyanophenoxy)benzene

Mass spectrometry data (m/z): 381 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 6.81 (1H, t), 6.92 (2H, d), 6.97 (2H, dd), 7.10 (2H, d), 7.45 (1H,t), 7.63 (2H, d)

(b) The following compound was obtained in the same manner as describedin Reference Example 22 (b).

1,3-Bis(3-chloro-4-formylphenoxy)benzene

Mass spectrometry data (m/z): 387 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 6.7-7.1 (7H, m), 7.47 (1H, t), 7.92 (2H, d), 10.35 (2H, s)

Reference Example 38

(a) The following compound was obtained in the same manner as describedin Reference Example 22 (a).

1,3-Bis(4-cyanophenoxy)-4,6-dichlorobenzene

Mass spectrometry data (m/z): 380 (M⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR33##

(b) The following compound was obtained in the same manner as describedin Reference Example 22 (b).

1,3-Bis(formylphenoxy)-4,6-dichlorobenzene

Mass spectrometry data (m/z): 386 (M⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR34##

Reference Example 39

(a) The following compound was obtained in the same manner as describedin Reference Example 22 (a).

1,3-Bis(4-cyanophenoxy)-4-ethylbenzene

Mass spectrometry data (m/z): 340 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.19 (3H, t, --CH₂ CH₃), 2,58 (2H, q, --CH₂ CH₃), 6.65-7.70 (11H, m,phenyl)

(b) The following compound was obtained in the same manner as describedin Reference Example 22 (b).

1,3-Bis(formylphenoxy)-4-ethylbenzene

Mass spectrometry data (m/z): 346 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.20 (3H, t, --CH₂ CH₃), 2.61 (2H, q, --CH₂ CH₃), 6.70-8.00 (11H, m,phenyl), 9.91 (2H, s, --CHO×2)

Reference Example 40

(a) The following compound was obtained in the same manner as describedin Reference Example 22 (a).

3,5-Bis(4-cyanophenoxy)benzamide

Mass spectrometry data (m/z): 355 (M⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR35##

(b) The following compound was obtained in the same manner as describedin Reference Example 22 (b).

3,5-Bis(4-formylphenoxy)benzamide

Mass spectrometry data (m/z): 362 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR36##

Reference Example 41

At room temperature, 11.4 g of 4-methylaminobenzonitrile dissolved indimethyl sulfoxide was added dropwise to a mixture of 11.6 g ofpotassium tert-butoxide and 100 ml of dimethyl sulfoxide. After 20minutes of stirring, 10.5 g of fluorobenzonitrile was added to thereaction mixture, and the stirring was continued for 30 minutes at roomtemperature. The whole mixture was poured into water, and the thusformed precipitate was collected by filtration, washed with water andethanol in that order and then dried to obtain 17.5 g ofN,N-bis(4-cyanophenyl)methylamine.

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 3.42 (3H, s), 7.10 (4H, d), 7.58 (4H, d)

Reference Example 42

Concentrated hydrochloric acid (45 ml) and ice were added to 21.7 g of4,4'-thiodianiline to which, with ice-cooling, was subsequently addeddropwise 50 ml of aqueous solution of 15.2 g sodium nitrite spending 30minutes. Five minutes thereafter, the reaction mixture was neutralizedwith sodium carbonate and added dropwise to 250 ml of ice-cooledwater-benzene (3:2) solution containing 22.4 g of copper (I) cyanide and38.2 g of potassium cyanide. The reaction mixture was stirred for 2hours while ice-cooling and then mixed with ethyl acetate to removeinsoluble materials by filtration. The resulting organic layer waswashed with saturated sodium chloride aqueous solution and dried overanhydrous magnesium sulfate. The solvent was evaporated under a reducedpressure, and the resulting residue was subjected to silica gelchromatography and to obtain 11.7 g of bis(4-cyanophenyl) sulfide fromfractions of chloroform elution.

Mass spectrometry data (m/z): 236 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 7.39 (4H, d), 7.53 (4H, d)

Example 1

(a) Sodium hydride (2.77 g, 60% oil dispersion) was washed with dryhexane and suspended in 200 ml of dimethylformamide to which wassubsequently added 15.6 g of benzyloxyurea in several portions at roomtemperature. The mixture was stirred for 20 minutes at the internaltemperature of 100° C. with heating in an oil bath. After cooling toroom temperature, 8.4 g of bis[(4-chloromethyl)phenyl] ether which hadbeen dissolved in 100 ml of dimethylformamide was added dropwise. Thereaction mixture was again heated and stirred at the internaltemperature of 100° C. for 30 minutes, ice-cooled, and then mixed with100 ml of 1N hydrochloric acid. The mixture was extracted with ethylacetate, and the resulting organic layer was washed with water andsaturated sodium chloride aqueous solution in that order and dried overanhydrous magnesium sulfate. The solvent was evaporated to obtain 15.4 gof crude crystals. By recrystallizing from 30 ml of ethanol, 8.5 g ofbis[[4-(N-carbamoyl-N-benzyloxyamino)methyl]phenyl]ether was obtained.

Mass spectrometry data (m/z): 527 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR37## 4.74 (4H, s, benzyl), 6.55 (4H, brs, --NH₂), 6.90-6.94 (4H, m,phenyl), 7.26-7.28 (4H, m, phenyl), 7.33-7.40 (10H, m, phenyl)

(b) Bis[[4-(N-carbamoyl-N-benzyloxyamino)methyl]phenyl]ether (5 g) wasdissolved in 200 ml of ethanol to which was subsequently added 0.5 g of10% palladium carbon. At room temperature, 9.58 g of ammonium formatewas added in several portions. After 2 hours of stirring, the reactionmixture was filtered with Celite, the residue was washed several timeswith a small volume of dimethylformamide, and then the filtrate and thewashed solutions were combined and the solvent was evaporated to effectformation of crude crystals, which were subsequently washed with ethanolto obtain 2.93 g ofbis[[4-(N-carbamoyl-N-hydroxyamino)methyl]phenyl]ether.

Mass spectrometry data (m/z): 347 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR38## 6.35 (4H, s, --NH₂ ×2), 6.93-6.96 (4H, m, phenyl), 7.27-7.30(4H, m, phenyl), 9.30-9.40 (2H, brs, N--OH)

(c) Bis[[4-(N-carbamoyl-N-hydroxyamino)methyl]phenyl]ether (2.93 g) wassuspended in 100 ml of tetrahydrofuran, and 25 ml of 2N sodium hydroxideaqueous solution was slowly added to the suspension with ice-cooling.When it became a uniform solution, 2.75 g of ethyl chloroformate wasadded dropwise, and the mixture was stirred at room temperature for 13hours. After adding 9 ml of 6N hydrochloric acid with ice-cooling, thereaction solution was extracted with ethyl acetate (200 ml×3), and theorganic layer was washed with water and saturated sodium chlorideaqueous solution in that order and dried over anhydrous magnesiumsulfate. The solvent was evaporated to obtain 2.77 g of crude crystals.They were recrystallized from a mixed solvent of 30 ml ethanol and 5 mldioxane to obtain 1.63 g ofbis-[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenyl]ether

Melting point: 175°-178° C.

Elemental analysis (for C₁₈ H₁₄ N₄ O₇)

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   54.28         3.54    14.07                                          found    53.96         3.69    13.59                                          ______________________________________                                    

Mass spectrometry data (m/z): 397 ([M-H]⁻)

Nuclear magnetic resonance spectrum. (DMSO-d₆, TMS internal standard)##STR39##

The following compounds of Examples 2 to 8 were synthesized in the samemanner as in Example 1.

Example 2 (a)Bis[4-[[(N-benzyloxy-N-carbamoyl)amino]methyl]phenyl]methane (b)Bis[4-[[(N-carbamoyl-N-hydroxy)amino]methyl]phenyl]methane

Mass spectrometry data (m/z): 345 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR40##

(c) Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenyl]methane

Melting point: 179°-180° C.

Elemental analysis (for C₁₉ H₁₆ N₄ O₆)

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   57.58         4.07    14.14                                          found    57.11         4.09    13.08                                          ______________________________________                                    

Mass spectrometry data (m/z): 395 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO, TMS internal standard)##STR41##

Example 3 (a)2,7-Bis[4-[[(N-benzyloxy-N-carbamoyl)amino]methyl]phenoxy]naphthalene

Melting point: 109°-113° C.

Mass spectrometry data (m/z): 669 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR42##

(b) 2,7-Bis[4-[[(N-carbamoyl-N-hydroxy)amino]methyl]phenoxy]naphthalene

Melting point: 188°-192° C.

Mass spectrometry data (m/z): 489 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR43##

(c)2,7-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]naphthalene

Melting point: 174°-176° C.

Mass spectrometry data (m/z): 539 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR44##

Example 4 (a)1,4-Bis[4-[[(N-benzyloxy-N-carbamoyl)amino]methyl]phenoxy]benzene

Melting point: 118°-122° C.

Mass spectrometry data (m/z): 619 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR45##

(b) 2,7-Bis[4-[[(N-carbamoyl-N-hydroxy)amino]methyl]phenoxy]benzene

Mass spectrometry data (m/z): 439 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR46##

(c)1,4-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]benzene

Mass spectrometry data (m/z): 489 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR47##

Example 5 (a)1,5-Bis[4-[[(N-benzyloxy-N-carbamoyl)amino]methyl]phenoxy]pentane

Mass spectrometry data (m/z): 613 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR48##

(b) 1,5-Bis[4-[[(N-carbamoyl-N-hydroxy)amino]methyl]phenoxy]pentane

Mass spectrometry data (m/z): 433 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR49##

(c)1,5-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]pentane

Starting compound:1,5-bis[4-[(N-carbamoyl-N-hydroxy)amino]methylphenoxy]pentane

Melting point: 156°-7° C.

Elemental analysis (for C₂₃ H₂₄ N₄ O₈)

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   57.02         4.99    11.56                                          found    56.82         4.94    11.62                                          ______________________________________                                    

Mass spectrometry data (m/z): 483 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR50##

Example 6 (a)1,3-Bis[4-[[(N-benzyloxy-N-carbamoyl)amino]methyl]phenoxy]benzene

Mass spectrometry data (m/z): 619 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)##STR51##

(b) 1,3-Bis[4-[[(N-carbamoyl-N-hydroxy)amino]ethyl]phenoxy]benzene (c)1,3-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]benzene

Starting compound:1,3-Bis[4-[(N-carbamoyl-N-hydroxyl)aminomethyl]phenoxy]benzene

Melting point: 174°-5° C.

Elemental analysis (for C₂₄ H₁₈ N₄ O₈)

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   58.78         3.70    11.42                                          found    58.69         3.73    11.13                                          ______________________________________                                    

Mass spectrometry data (m/z): 489 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR52##

Example 7 (a)Trans-1,4-bis[[4-[[(N-benzyloxy-N-carbamoyl)amino]methyl]phenoxy]methyl]cyclohexane

Mass spectrometry data (m/z): 653 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR53##

(b)Trans-1,4-bis[[4-[[(N-carbamoyl-N-hydroxy)amino]methyl]phenoxy]methyl]cyclohexane

Mass spectrometry data (m/z): 473 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR54##

(c)Trans-1,4-bis[[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]methyl]cyclohexane

Starting compound:trans-1,4-bis[[4-[(N-carbamoyl-N-hydroxy)aminomethyl]phenoxy]methyl]cyclohexane

Melting point: 175°-6° C.

Elemental analysis (for C₂₆ H₂₈ N₄ O₈)

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   59.54         5.38    10.68                                          found    59.67         5.48    10.07                                          ______________________________________                                    

Mass spectrometry data (m/z): 523 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR55##

Example 8 (a)Cis-1,3-bis[4-[[(N-benzyloxy-N-carbamoyl)amino]methyl]phenoxy]cyclohexane(b)Cis-1,3-bis[4-[[(N-carbamoyl-N-hydroxy)amino]methyl]phenoxy]cyclohexane(c)Cis-1,3-bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]cyclohexane

Starting compound:cis-1,3-bis[4-[(N-carbamoyl-N-hydroxy)aminomethyl]phenoxy]cyclohexaneAmorphous

Mass spectrometry data (m/z): 495 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR56##

Example 9 (a)1,2-Bis[4-[[(N-benzyloxy-N-carbamoyl)amino]methyl]phenoxy]benzene (b)1,2-Bis[4-[[(N-carbamoyl-N-hydroxy)amino]methyl]phenoxy]benzene (c)1,2-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]benzene

Melting point: 105°-112° C.

Elemental analysis (for C₂₄ H₁₈ N₄ O₈.1.4H₂ O)

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   55.90         4.07    10.87                                          found    56.14         3.95    10.53                                          ______________________________________                                    

Mass spectrometry data (m/z): 487 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR57##

Example 10

(a) The mixture of (Z)-1,4bis(4-formylphenoxy)-2-butene (9.85 g),hydroxylamine, hydrochloride (6.91 g) and sodium acetate (8.20 g) inwater methanol (12:88) (225 ml) was subjected to 0.5 hour of heatingunder reflux, the solvent was evaporated under a reduced pressure andthen the thus obtained residue was diluted with water and extracted withethyl acetate. The organic layer was washed with saturated sodiumchloride aqueous solution and dried over anhydrous magnesium sulfate.The solvent was evaporated under a reduced pressure to obtain the crudeproduct of (Z)-1,4-bis[4-(N-hydroxyiminomethyl)phenoxy]-2-butene (10.4g). The thus obtained crude product (1.74 g) was dissolved inethanol-tetrahydrofuran (1:2) (60 ml) and, with ice-cooling, to thesolution was added borane-pyridine complex (1.1 ml) and the mixture wasstirred for 1.25 hours. 10% Hydrochloric acid (12 ml) was added dropwiseto the reaction mixture, and the mixture was subsequently stirred for0.5 hour with ice-cooling and 4.5 hours at room temperature and thenmixed with saturated potassium carbonate aqueous solution. The solventwas evaporated under a reduced pressure, and the thus obtained residuewas diluted with water and extracted with chloroform. The organic layerwas washed with saturated sodium chloride aqueous solution and driedover anhydrous magnesium sulfate, and the solvent was subsequentlyevaporated under a reduced pressure. The resulting residue was purifiedby silica gel column chromatography with chloroform-methanol (50:1)elution to obtain (Z)-1,4-bis[4-(N-hydroxyaminomethyl)phenoxy]-2-butene(0.86 g).

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 3.79 (4H, s), 4.69 (4H, d), 5.8-5.9 (4H, m), 6.88 (4H, d), 7.24 (4H,d)

(b) Concentrated hydrochloric acid (1 ml) was added dropwise to thesolution of (Z)-1,4-Bis[4-(N-hydroxyaminomethyl)phenoxy]-2-butene (0.86g) in methanol-tetrahydrofuran (1:1) (40 ml), 1N potassium cyanateaqueous solution (7.5 ml) was added to the mixture, followed by stirringat room temperature for 1.25 hours. The solvent was evaporated under areduced pressure, and the thus obtained residue was adjusted to pH 10 byadding 1N sodium hydroxide aqueous solution and extracted with ethylacetate. The organic layer was washed with saturated sodium chlorideaqueous solution and dried over anhydrous magnesium sulfate, and thenthe solvent was evaporated under a reduced pressure to obtain the crudeproduct of (Z)-1,9-bis[4-[(1-hydroxyureido)methyl]phenoxy]-2-butene(1.02 g).

(c) To the solution of(Z)-1,4-Bis[4-[(1-hydroxyureido)methyl]phenoxy]-2-butene (0.75 g) intetrahydrofuran (20 ml) was added 2N sodium hydroxide aqueous solution(6.9 ml) and then, with ice-cooling, ethyl chloroformate (0.66 ml) wasadded dropwise to the mixture. After 49 hours of stirring at roomtemperature, the reaction mixture was adjusted to pH 1 with 6Nhydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with saturated sodium chloride aqueous solution and driedover anhydrous magnesium sulfate and then the solvent was evaporatedunder a reduced pressure. The resulting residue was subjected to silicagel column chromatography with chloroform-methanol (10:1) elution, andthe obtained crude product was recrystallized from methanol to obtain(Z)-1,4-bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]-2-butene(0.31 g).

Product of (b)

Mass spectrometry data (m/z): 417 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.43 (4H, s), 4.70 (4H, d), 5.87 (2H, t), 6.52 (4H, s), 6.89 (4H, d),7.20 (4H, d), 9.24 (2H, s)

Product of (c)

Melting point: 139°-144° C.

Elemental analysis (for C₂₂ H₂₀ N₄ O₈)

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   56.41         4.30    11.96                                          found    56.25         4.24    11.85                                          ______________________________________                                    

Mass spectrometry data (m/z):467 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.73 (4H, d), 5.87 (2H, t), 6.98 (4H, d), 7.26 (4H, d), 12.42 (2H, brs)

Example 11

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

1,9-Bis[4-(hydroxyaminomethyl)phenoxy]nonane

Starting compound: 1,9-bis(formylphenoxy)nonene

Mass spectrometry data (m/z): 403 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:1.25-1.45 (10H, m), 1.65-1.75 (4H, m), 3.33 (2H, s), 3.77 (4H, s), 3.92(4H, t), 6.85 (4H, d), 7.29 (4H, d)

(b) 1,9-Bis[4-(hydroxyaminomethyl)phenoxy]nonane (1.07 g) was dissolvedin 75 ml of tetrahydrofuran-dimethylformamide (4:1) and, in anatmosphere of argon and with ice-cooling, 0.75 ml of ethoxycarbonylisocyanate was added dropwise to the solution. After 10 minutes ofstirring, 1N sodium hydroxide aqueous solution was added dropwise to thereaction mixture with water-cooling, followed by 2 hours of stirring atroom temperature. The solvent was evaporated under a reduced pressure,and the thus obtained residue was mixed with 1N hydrochloric acid andthe mixture was extracted with ethyl acetate. The organic layer waswashed with water and saturated sodium chloride aqueous solution in thatorder and dried over anhydrous magnesium sulfate. Then, the solvent wasevaporated under a reduced pressure. The resulting residue was subjectedto silica gel column chromatography, and the thus obtained 0.78 g ofcrude product obtained from fractions of chloroform-methanol (40:1)elution was recrystallized from methanol to obtain 0.69 g of1,9-bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]nonane.

Melting point: 149°-151° C.

Elemental analysis (for C₂₇ H₃₂ N₄ O₈)

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   59.99         5.97    10.36                                          found    60.00         5.98    10.36                                          ______________________________________                                    

Mass spectrometry data (m/z): 541 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:1.25-1.45 (14H, m), 3.95 (4H, t), 4.70 (9H, s), 6.92 (4H, d), 7.23 (4H,d), 12.42 (2H, brs)

Example 12

(a) 1,4-Bis(4-formylphenoxy)butane (3.98 g) was dissolved in 10.5 ml oftetrahydrofuran-methanol (5:1), 1.23 g of sodium borohydride was addedto the solution which was cooled on ice-water, and the resulting mixturewas stirred for 1.5 hours at room temperature. Then, 100 ml of 1Nhydrochloric acid was added and the mixture was again stirred at roomtemperature to collect the thus formed precipitate by filtration. Thethus obtained crude product was washed with water and methanol in thatorder and dried under a reduced pressure to obtain 3.38 g of1,4-bis(4-hydroxymethylphenoxy)butane.

(b) 1,4-Bis(4-hydroxymethylphenoxy)butane (1.78 g) was added to 25 ml of4N hydrochloric acid-dioxane solution. The mixture was stirred for 0.5hour at 65° C., the solvent was evaporated under a reduced pressure.Then, the resulting residue was washed with water and methanol in thatorder and dried under a reduced pressure to obtain 1.95 g of1,4-bis(4-chloromethylphenoxy)butane.

Product of (a)

Mass spectrometry data (m/z): 302 (M⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:3.80-4.20 (4H, m), 4.39 (4H, d), 5.01 (2H, t), 6.87 (4H, d), 7.20 (4H,d)

Product of (b)

Mass spectrometry data (m/z): 338 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard) δ:1.85-2.15 (4H, m), 3.97-4.10 (4H, m), 4.56 (4H, s), 6.85 (4H, d), 7.29(4H, d)

(c) 60% Sodium hydride (0.41 g) and 1.71 g of benzyloxyurea were addedto 20 ml of dimethylformamide and the mixture was stirred at 80° C. for7.5 hours. 1,4-Bis(4-chloromethylphenoxy)butane (1.74 g) was added tothe reaction mixture at room temperature and the mixture was stirred at95° C. for 0.5 hour. The reaction product was cooled to roomtemperature, poured into ice water, mixed with 1N hydrochloric acid andthen extracted with ethyl acetate. The organic layer was washed withwater and saturated sodium chloride aqueous solution in that order anddried over anhydrous magnesium sulfate and then the solvent wasevaporated under a reduced pressure. The resulting crude product waswashed with ethyl acetate to obtain 1.94 g of1,4-bis[4-[(1-benzyloxyureido)methyl]phenoxy]butane.

(d) 1,4-Bis[4-[(1-benzyloxyureido)methyl]phenoxy]butane (1.94 g) wasdissolved in 45 ml of dimethylformamide-ethanol (8:1), mixed with 0.29 gof 10% palladium carbon and then the mixture was stirred for 22 hours atroom temperature in an atmosphere of hydrogen. The catalyst was removedby filtration using Celite, and the solvent was evaporated under areduced pressure to obtain 0.84 g of1,4-bis[4-[(1-hydroxyureido)methyl]phenoxy]butane.

Product of (c)

Mass spectrometry data (m/z): 599 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:1.78-1.90 (4H, m), 3.90-4.00 (4H, m), 4.43 (4H, s), 4.72 (4H, s), 6.49(4H, s), 6.68 (4H, d), 7.18 (4H, d), 7.33-7.39 (10H, m)

Product of (d)

Mass spectrometry data (m/z): 419 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:1.78-1.90 (4H, m), 3.95-4.05 (4H, m), 4.43 (4H, s), 6.29 (4H, s), 6.87(4H, d), 7.18 (4H, d), 9.26 (2H, s)

(e) The following compound was obtained in the same manner as describedin Example 10 (c).

1,4-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]butane

Starting compound: 1,4-bis[4-[(1-benzyloxyureido)methyl]phenoxy]butane

Melting point: 188°-192° C.

Mass spectrometry data (m/z): 469 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:1.80-1.95 (4H, m), 3.90-4.10 (4H, m), 4.71 (4H, s), 6.94 (4H, d), 7.24(4H, d), 12.42 (2H, brs)

Example 13

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

1,6-Bis[4-(hydroxyaminomethyl)phenoxy]hexane

Mass spectrometry data (m/z): 360 (M⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:1.20-1.80 (8H, m), 3.65-4.10 (8H, m), 5.85 (2H, t), 6.85 (4H, d), 7.22(4H, d)

(b) The following compound was obtained in the same manner as describedin Example 10 (b).

1,6-Bis[4-[(1-hydroxyureido)methyl]phenoxy]hexane

Mass spectrometry data (m/z): 447 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:1.20-2.00 (8H, m), 3.94 (4H, t), 4.43 (4H, s), 6.24 (4H, s), 6.85 (4H,d), 7.18 (4H, d), 9.25 (2H, s)

(c) The following compound was obtained in the same manner as describedin Example 10 (c).

1,6-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]hexane

Melting point: 171°-176° C.

Elemental analysis (for C₂₄ H₂₆ N₄ O₈)

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   57.83         5.26    11.24                                          found    57.52         5.23    10.96                                          ______________________________________                                    

Mass spectrometry data (m/z): 497 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:1.40-1.50 (4H, m), 1.65-1.75 (4H, m), 3.97 (4H, t), 4.71 (4H, s), 6.93(4H, d), 7.24 (4H, d), 12.42 (2H, brs)

Example 14

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

(E)-1,4-bis[4-(hydroxyaminomethyl)phenoxy]-2-butene

Mass spectrometry data (m/z): 331 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:3.79 (4H, m), 4.57 (4H, s), 5.85 (2H, brs), 6.03-6.05 (2H, m), 6.87 (4H,d), 7.23 (4H, d)

(b) The following compound was obtained in the same manner as describedin Example 10 (b).

(E)-1,4-bis[4-[(1-hydroxyureido)methyl]phenoxy]-2-butene

Mass spectrometry data (m/z): 417 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.44 (4H, m), 4.58 (4H, s), 6.05 (2H, s), 6.31 (4H, s), 6.88 (4H, d),7.19 (4H, d), 9.68 (2H, brs)

(c) The following compound was obtained in the same manner as describedin Example 10 (c).

(E)-1,4-bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]-2-butene

Melting point: 184°-189° C.

Elemental analysis (for C₂₂ H₂₀ N₄ O₈)

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   56.41         4.30    11.96                                          found    56.18         4.46    11.74                                          ______________________________________                                    

Mass spectrometry data (m/z): 467 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.60 (4H, t), 4.71 (4H, s), 6.06 (2H, s), 6.96 (4H, d), 7.26 (4H, d),12.42 (2H, brs)

Example 15

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

1,7-Bis[4-(hydroxyaminomethyl)phenoxy]heptane

Mass spectrometry data (m/z): 374 (M⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:1.30-1.50 (6H, m), 1.65-1.85 (4H, m), 3.92-3.98 (8H, m), 6.89 (4H, d),7.30 (4H, d), 9.10 (2H, brs)

(b) The following compound was obtained in the same manner as describedin Example 10 (b).

1,7-Bis[4-[(1-hydroxyureido)methyl]phenoxy]heptane

Mass spectrometry data (m/z): 461 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:1.30-1.50 (6H, m), 1.65-1.85 (4H, m), 3.95 (4H, t), 4.42 (4H, s), 6.29(2H, s), 6.86 (4H, d), 7.17 (4H, d), 9.25 (2H, s)

(c) The following compound was obtained in the same manner as describedin Example 10 (c).

1,7-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]heptane

Melting point: 136°-139° C.

Elemental analysis (for C₂₅ H₂₈ N₄ O₈)

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   58.59         5.51    10.93                                          found    58.34         5.53    10.79                                          ______________________________________                                    

Mass spectrometry data (m/z): 511 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:1.30-1.50 (6H, m), 1.60-1.85 (4H, m), 3.97 (4H, t), 4.71 (4H, s), 6.92(4H, d), 7.24 (4H, d), 12.40 (2H, brs)

Example 16

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

1,3-Bis[4-(hydroxyaminomethyl)phenoxy]methyl]benzene

Mass spectrometry data (m/z): 381 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:3.78 (4H, s), 5.10 (4H, s), 5.86 (2H, s), 6.95 (4H, d), 7.23 (4H, d),7.40 (3H, s), 7.52 (1H, s)

(b) The following compound was obtained in the same manner as describedin Example 10 (b).

1,3-Bis[[4-[(1-hydroxyureido)methyl]phenoxy]methyl]benzene

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.44 (4H, s), 5.12 (4H, s), 6.30 (4H, s), 6.95 (4H, d), 7.20 (4H, d),7.40 (3H, s), 7.53 (1H, s), 9.51 (2H, brs)

(c) The following compound was obtained in the same manner as describedin Example 10 (c).

1,3-Bis[[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]methyl]benzene

Melting point: 189°-193° C.

Elemental analysis (for C₂₆ H₂₂ N₄ O₈.0.5H₂ O)

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   59.20         4.39    10.62                                          found    59.16         4.29    10.47                                          ______________________________________                                    

Mass spectrometry data (m/z): 517 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.69 (4H, s), 5.12 (4H, s), 7.01 (4H, d), 7.26 (4H, d), 7.41 (3H, s),7.54 (1H, s)

Example 17

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

1,5-Bis[4-(hydroxyaminomethyl)phenoxy]-3,3-dimethylpentane

Mass spectrometry data (m/z): 375 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard) δ:1.04 (6H, s), 1.79 (4H, t), 3.92 (4H, s), 4.02 (4H, t), 6.83 (4H, d),7.21 (4H, d), 7.26 (2H, s)

(b) The following compound was obtained in the same manner as describedin Example 11 (b).

1,5-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]-3,3-dimethylpentane

Mass spectrometry data (m/z): 511 ([M-H]⁻)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard) δ:1.07 (6H, s), 1.81 (4H, t), 4.06 (4H, t), 4.73 (4H, s), 6.81 (4H, d),7.24 (4H, d)

Example 18

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

Cis-1,3-bis[4-(hydroxyaminomethyl)phenoxy]cyclopentane

Mass spectrometry data (m/z): 345 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:1.75-1.90 (2H, m), 2.05-2.25 (4H, m), 3.32 (4H, s), 3.77 (4H, s), 4.95(2H, s), 5.84 (2H, brs), 6.84 (4H, d), 7.22 (4H, d)

(b) The following compound was obtained in the same manner as describedin Example 11 (b).

Cis-1,3-bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]cyclopentane

Melting point: 151°-159° C.

Elemental analysis (for C₂₃ H₂₂ N₄ O₈)

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   57.26         4.60    11.61                                          found    57.35         4.70    11.30                                          ______________________________________                                    

Mass spectrometry data (m/z): 481 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:1.75-1.90 (2H, m), 2.05-2.30 (4H, m), 4.71 (4H, s), 4.90-5.05 (2H, m),6.93 (4H, d), 7.24 (2H, brs), 12.42 (2H, brs)

Example 19

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

Trans-1,3-bis[4-(hydroxyaminomethyl)phenoxy]cyclopentane

Mass spectrometry data (m/z): 344 (M⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:1.95-2.20 (6H, m), 3.91 (4H, s), 3.95-4.15 (2H, m), 4.70-4.85 (2H, m),6.82 (4H, d), 7.18 d)

(b) The following compound was obtained in the same manner as describedin Example 11 (b).

Trans-1,3-bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]cyclopentane

Mass spectrometry data (m/z): 481 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:1.74-1.78 (2H, m), 1.80-1.95 (2H, m), 1.95-2.10 (2H, m), 4.30 (4H, s),4.75-4.85 (2H, m), 6.84 (4H, d), 7.16 (4H, d)

Example 20

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

1,8-Bis[4-(hydroxyaminomethyl)phenoxy]octane

Mass spectrometry data (m/z): 389 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:1.25-1.50 (8H, m), 1.65-1.75 (4H, m), 3.78 (4H, s), 3.92 (4H, t), 6.83(4H, d), 7.21 (4H, d)

(b) The following compound was obtained in the same manner as describedin Example 11 (b).

1,8-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]octane

Melting point: 160°-163° C.

Elemental analysis (for C₂₆ H₃₀ N₄ O₈)

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   59.31         5.74    10.64                                          found    59.22         5.88    10.29                                          ______________________________________                                    

Mass spectrometry data (m/z): 525 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:1.25-1.45 (8H, m), 1.65-1.75 (4H, m), 3.95 (4H, t), 4.70 (4H, s), 6.92(4H, d), 7.24 (4H, d), 12.40 (2H, brs)

Example 21

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

2,2-Bis[4-(hydroxyaminomethyl)phenoxy]ethyl ether

Mass spectrometry data (m/z): 349 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:3.74-3.82 (4H, m), 3.78 (4H, s), 4.07 (4H, t), 5.84 (2H, s), 6.87 (4H,d), 7.23 (4H, d)

(b) The following compound was obtained in the same manner as describedin Example 11 (b).

2,2-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]ethylether

Melting point: 92°-95° C.

Elemental analysis (for C₂₂ H₂₂ N₄ O₉)

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   54.34         4.94    10.56                                          found    54.05         4.91    10.51                                          ______________________________________                                    

Mass spectrometry data (m/z): 485 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:3.81 (4H, t), 4.11 (4H, t), 4.71 (4H, s), 6.95 (4H, d), 7.25 (4H, d),12.45 (2H, brs)

Example 22

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

1,2-Bis[4-(hydroxyaminomethyl)phenoxy]ethane

Mass spectrometry data (m/z): 305 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:3.97 (4H, s), 4.10-4.50 (2H, m), 4.30 (4H, s), 6.95 (4H, d), 7.34 (4H,d)

(b) The following compound was obtained in the same manner as describedin Example 11 (b).

1,2-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]ethane

Melting point: 203°-206° C.

Elemental analysis (for C₂₀ H₁₈ N₄ O₈)

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   54.30         4.10    12.66                                          found    54.09         4.13    12.55                                          ______________________________________                                    

Mass spectrometry data (m/z): 441 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.32 (4H, s), 4.72 (4H, s), 6.99 (4H, d), 7.27 (4H, d), 12.42 (2H, brs)

Example 23

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

1,3-Bis[4-(hydroxyaminomethyl)phenoxy]propane

Mass spectrometry data (m/z): 319 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:2.16 (2H, quint), 3.99 (4H, s), 3.90-4.20 (6H, m), 6.91 (4H, d), 7.31(4H, d)

(b) The following compound was obtained in the same manner as describedin Example 11 (b).

1,3-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]propane

Melting point: 176°-178° C.

Elemental analysis (for C₂₁ H₂₀ N₄ O₈)

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   55.26         4.42    12.28                                          found    55.10         4.33    12.05                                          ______________________________________                                    

Mass spectrometry data (m/z): 455 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:2.16 (2H, quint), 4.13 (4H, t), 4.71 (4H, t), 4.71 (4H, s), 6.96 (4H,d), 7.25 (4H, d), 12.41 (2H, brs)

Example 24

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

1,10-Bis[4-(hydroxyaminomethyl)phenoxy]decane

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:0.90-1.90 (12H, m), 2.40-2.60 (4H, m), 3.80 (4H, m), 3.60-4.35 (6H, m),6.83 (4H, s), 6.83 (4H, d), 7.22 (4H, d)

(b) The following compound was obtained in the same manner as describedin Example 11 (b).

1,10-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]decane

Melting point: 153°-158° C.

Elemental analysis (for C₂₈ H₃₄ N₄ O₈)

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   60.64         6.18    10.10                                          found    60.55         6.22    9.59                                           ______________________________________                                    

Mass spectrometry data (m/z): 553 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:1.20-1.40 (12H, m), 1.60-1.75 (4H, m), 3.95 (4H, t), 4.70 (4H, t), 6.92(4H, d), 7.24 (4H, d), 12.41 (2H, brs)

Example 25

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

1,11-Bis[4-(hydroxyaminomethyl)phenoxy]undecane

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:0.90-1.90 (14H, m), 2.40-2.65 (4H, m), 3.83 (4H, s), 3.60-4.20 (6H, m),6.84 (4H, d), 7.23 (4H, d)

(b) The following compound was obtained in the same manner as describedin Example 11 (b).

1,11-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]undecane

Melting point: 122°-125° C.

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:1.20-1.45 (14H, m), 1.60-1.75 (4H, m), 3.94 (4H, t), 4.69 (4H, s), 6.91(4H, d), 7.23 (4H, d)

Example 26

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

1,12-Bis[4-(hydroxyaminomethyl)phenoxy]dodecane

Mass spectrometry data (m/z): 445 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:1.00-1.90 (20H, m), 3.60-4.10 (10H, m), 6.86 (4H, d), 7.27 (4H, d)

(b) The following compound was obtained in the same manner as describedin Example 11 (b).

1,12-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]dodecane

Melting point: 220°-228° C.

Mass spectrometry data (m/z): 558 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:1.20-1.45 (16H, m), 1.63-1.75 (4H, m), 3.93 (4H, t), 4.52 (4H, s), 6.83(4H, d), 7.20 (4H, d)

Example 27

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

1,5-Bis[4-(hydroxyaminomethyl)phenoxy]-2,2,3,3,4,4-hexafluoropentane

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:3.81 (4H, s), 4.72 (4H, t), 5.89 (4H, s), 6.99 (4H, d), 7.28 (4H, d)

(b) The following compound was obtained in the same manner as describedin Example 11 (b).

1,5-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenyl]-2,2,3,3,4,4-hexafluoropentane

Melting point: 128°-131° C.

Mass spectrometry data (m/z): 591 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.74 (4H, s), 4.78 (4H, t), 7.08 (4H, d), 7.30 (4H, d), 12.44 (2H, brs)

Example 28

(a) Under cooling at -70° C., 24 ml of 1.6M butyllithium-hexane solutionwas added dropwise to 40 ml of tetrahydrofuran solution containing 6.48g of 4-bromotoluene. After 1 hour of stirring at -70° C., 20 ml oftetrahydrofuran solution containing 4.33 g ofN,N-dimethyl-N',N'-dimethoxyisophthaldiamide were added dropwise to thereaction mixture. After 2 hours of stirring at 70° C. the reactionmixture was diluted with 1N hydrochloric acid and extracted with ethylacetate. The organic layer was washed with water and saturated sodiumchloride aqueous solution and dried over anhydrous magnesium sulfate.The solvent was evaporated under a reduced pressure, and the resultingresidue was recrystallized from hexane-ethyl acetate to obtain 3.18 g of1,3-ditoluoylbenzene.

Mass spectrometry data (m/z): 315 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:2.42 (6H, s), 7.39 (4H, d), 7.71 (4H, d), 7.76 (1H, t), 7.95-8.02 (3H,m)

(b) To 60 ml of carbon tetrachloride solution containing 1.82 g of1,3-ditoluoylbenzene were added 2.27 g of N-bromosuccinimide and 0.15 gof azoisobutyrobenzonitrile. The reaction mixture was heated underreflux for 2 days and then insoluble materials were removed byfiltration. The solvent was evaporated under a reduced pressure, and theresulting residue was recrystallized from hexane-ethyl acetate to obtain1.63 g of 1,3-bis(4-bromomethylbenzoyl)benzene.

Mass spectrometry data (m/z): 471 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.80 (4H, s), 7.65 (4H, d), 7.76-7.86 (5H, m), 7.99-8.08 (3H, m)

(c) The following compound was obtained in the same manner as describedin Example 12 (c).

1,3-Bis[4-[(1-benzyloxyureido)methyl]benzoyl]benzene

Starting compound: 1,3-bis(4-bromomethylbenzoyl)benzene

Mass spectrometry data (m/z): 643 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard) δ:4.71-4.72 (4H, m), 4.75-4.77 (4H, m), 7.28-7.49 (14H, m), 7.60-7.74 (5H,m), 7.98-8.18 (3H, m)

(d) Using a hydroxyurea compound obtained in the same manner asdescribed in Example 12 (d), the following compound was obtained in thesame manner as Example 10 (c).

1,3-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]benzyl]benzene

Starting compound: 1,3-bis[4-[(1-benzyloxyureido)methyl]benzoyl]benzene

Melting point: 230° C. (decomposition)

Mass spectrometry data (m/z): 485 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:3.88 (4H, s), 4.45 (4H, s), 7.01 (2H, d), 7.12-7.21 (10H, m)

Example 29

(a) The following compound was obtained in the same manner as describedin Example 12 (c).

1-Benzyloxy-1-(4-nitrobenzyl)urea

Starting compounds: 4-nitrobenzyl bromide, benzyloxyurea

Mass spectrometry data (m/z): 302 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard) δ:4.71 (2H, s), 4.76 (2H, s), 5.24 (2H, brs), 7.27-7.40 (5H, m), 7.47 (2H,d), 8.18 (2H, d)

(b) 10% Palladium carbon (0.3 g) was added to 80 ml of ethyl acetatesolution containing 4.76 g of 1-benzyloxy-1-(4-nitrobenzyl)urea. Thereaction mixture was stirred overnight under normal pressure in anatmosphere of hydrogen, and then insoluble materials were removed byfiltration. After evaporating the solvent under a reduced pressure, theresulting residue was purified by silica gel column chromatography(eluant: chloroform:methanol=10:1) to obtain 1.82 g of1-(4-aminobenzyl)-1-benzyloxyurea.

Mass spectrometry data (m/z): 272 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard) δ:4.54 (2H, s), 4.65 (2H, s), 5.19 (2H, brs), 6.65 (2H, d), 7.17 (2H, d),7.26-7.29 (2H, m), 7.33-7.37 (3H, m)

(c) With ice-cooling, 15 ml of dichloromethane solution containing 0.70g of isophthalic acid dichloride was added dropwise to 30 ml ofdichloromethane solution containing 1.79 g of1-(4-aminobenzyl)-1-benzyloxyurea and 0.71 g of triethylamine. Thereaction mixture was stirred overnight at room temperature and thenmixed with 1N hydrochloric acid. The thus formed crystals were collectedby filtration, washed with water and dichloromethane and then dried toobtain 1.54 g ofN,N'-bis[4-[(1-benzyloxyureido)methyl]phenyl]isophthalic acid amide.

Mass spectrometry data (m/z): 673 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.51 (4H, s), 4.75 (4H, s), 6.53 (4H, s), 7.27 (4H, d), 7.33-7.42 (10H,m), 7.68 (1H, t), 8.12 (2H, d), 8.51 (1H, s), 10.40 (2H, s)

(d) Ammonium formate (2 g) and 0.3 g of 10% palladium carbon were addedto 30 ml of dimethylformamide and 30 ml of ethanol solution containing1.53 g of N,N'-bis[4-[(1-benzyloxyureido)methyl]phenyl]isophthalic acidamide. The reaction mixture was stirred overnight at room temperatureand then insoluble materials were removed by filtration. The solvent wasevaporated under a reduced pressure, and water was added to theresulting residue. The thus formed insoluble substance was collected byfiltration, washed with water and diethyl ether and then dried to obtain0.52 g of N,N'-bis[4-[(1-hydroxyureido)methyl]phenyl]isophthalic acidamide.

Mass spectrometry data (m/z): 493 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.45 (4H, s), 6.35 (4H, s), 7.28 (4H, d), 7.67-7.75 (5H, m), 8.14 (2H,d), 8.53 (1H, s), 9.33 (2H, s), 10.40 (2H, s)

(e) The following compound was obtained in the same manner as describedin Example 10 (c).

N,N'-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenyl]isophthalicacid amide

Starting compound:N,N'-bis[4-[(1-hydroxyureido)methyl]phenyl]isophthalic acid amide

Melting point: 300° C. (decomposition)

Mass spectrometry data (m/z): 543 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.78 (4H, s), 7.35 (4H, d), 7.70 (1H, t), 7.81 (4H, d), 8.14 (2H, d),8.53 (1H, s), 10.50 (2H, s), 12.44 (2H, s)

Example 30

(a) The following compound was obtained in the same manner as describedin Example 12 (c).

1,3-Bis[4-[[1-(4-methoxybenzyloxy)ureido]methyl]benzoyl]benzene

Starting compounds: 1,3-bis(4-bromomethylbenzoyl)benzene,4-methoxybenzyloxyurea

Mass spectrometry data (m/z): 703 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:3.73 (6H, s), 4.62 (4H, s), 4.71 (4H, s), 6.58 (4H, s), 6.90 (4H, d),7.32 (4H, d), 7.43 (4H, d), 7.74-7.75 (5H, m), 7.98-8.02 (3H, m)

b) With ice-cooling, 10 ml of anisole and 40 ml of trifluoroacetic acidwere added to 1.47 g of1,3-bis[4-[[1-(4-methoxybenzyloxy)ureido]methyl]benzoyl]benzene. Thereaction mixture was stirred with ice-cooling for 30 minutes and then atroom temperature for 6 hours. The solvent was evaporated under a reducedpressure and the resulting residue was mixed with diethyl ether. Thethus formed crystals were collected by filtration and dried to obtain0.79 g of 1,3-bis[4-[(1-hydroxyureido)methyl]benzoyl]benzene.

Mass spectrometry data (m/z): 463 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.63 (4H, s), 6.44 (4H, s), 7.48 (4H, d), 7.76-7.79 (5H, m), 7.99-8.04(3H, m), 9.48 (2H, s)

(c) The following compound was obtained in the same manner as describedin Example 10 (c).

1,3-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]benzoyl]benzene

Starting compound: 1,3-bis[4-[(1-hydroxyureido)methyl]benzoyl]benzene

Melting point: 183°-185° C.

Mass spectrometry data (m/z): 513 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.93 (4H, s), 7.56 (4H, d), 7.79 (1H, t), 7.83 (4H, d), 8.01-8.06 (3H,m), 12.52 (2H, s)

Example 31

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

1,3-Bis[4-(hydroxyaminomethyl)phenoxy]-4-nitrobenzene

Starting compound: 1,3-bis(4-formylphenoxy)-4-nitrobenzene

Mass spectrometry data (m/z): 398 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard) δ:3.82 (4H, br), 6.25 (1H, d), 6.58 (1H, dd), 6.84 (2H, d), 6.86 (2H, d),7.13 (2H, d), 7.20 (2H, d), 7.89 (1H, d)

(b) The following compound was obtained in the same manner as describedin Example 10 (b).

1,3-Bis[4-[(1-hydroxyureido)methyl]phenoxy]-4-nitrobenzene

Starting compound: 1,3-bis[4-(hydroxyaminomethyl)phenoxy]-4-nitrobenzene

Mass spectrometry data (m/z): 484 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.51 (2H, s), 4.52 (2H, s), 6.38 (4H, s), 6.58 (1H, d), 6.76 (1H, dd),7.11 (2H, d), 7.12 (2H, d), 7.33 (2H, d), 7.35 (2H, d), 8.14 (1H, d),9.36 (1H, s), 9.38 (1H, s)

(c) The following compound was obtained in the same manner as describedin Example 10 (c).

1,3-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]-4-nitrobenzene

Starting compound:1,3-bis[4-[(1-hydroxyureido)methyl]phenoxy]-4-nitrobenzene

Melting point: 187°-189° C. (MeOH)

Elemental analysis (for C₂₄ H₁₇ N₅ O₁₀)

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   53.84         3.20    13.08                                          found    53.83         3.26    12.95                                          ______________________________________                                    

Mass spectrometry data (m/z): 534 ([M-H]° )

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.79 (2H, s), 4.81 (2H, s), 6.70 (1H, d), 6.85 (1H, dd), 7.12 (2H, d),7.20 (2H, d), 7.40 (2H, d), 7.43 (2H, d), 8.17 (1H, d)

Example 32

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

1,3-Bis[4-(hydroxyaminomethyl)phenoxy]-5-chlorobenzene

Starting compound: 1,3-bis(4-formylphenoxy)-5-chlorobenzene

Mass spectrometry data (m/z): 387 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:3.87 (4H, s), 6.52 (1H, t), 6.78 (2H, d), 7.04 (4H, d), 7.40 (4H, d)

(b) The following compound was obtained in the same manner as describedin Example 10 (b).

1,3-Bis[4-[(1-hydroxyureido)methyl]phenoxy]-5-chlorobenzene

Starting compound:1,3-bis[4-(hydroxyaminomethyl)phenoxy]-5-chlorobenzene

Mass spectrometry data (m/z): 473 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.52 (4H, s), 6.38 (4H, s), 6.35 (1H, t), 6.69 (2H, d), 7.07 (4H, d),7.34 (4H, d), 9.37 (2H, s)

(c) The following compound was obtained in the same manner as describedin Example 10 (c).

1,3-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]-5-chlorobenzene

Starting compound:1,3-bis[4-[(1-hydroxyureido)methyl]phenoxy]-5-chlorobenzene

Melting point: 84°-86° C., i-Pr₂ O

Elemental analysis (for C₂₄ H₁₇ N₄ O₈ Cl.H₂ O)

    ______________________________________                                               C (%) H (%)       N (%)   Cl (%)                                       ______________________________________                                        calcd.   53.10   3.53        10.32 6.53                                       found    53.08   3.47        10.14 6.40                                       ______________________________________                                    

Mass spectrometry data (m/z): 523 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.79 (4H, s), 6.61 (1H, t), 6.80 (2H, d), 7.13 (4H, d), 7.40 (4H, d)

Example 33

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

2,6-Bis[4-(hydroxyaminomethyl)phenoxy]benzonitrile

Starting compound: 2,6-bis(4-formylphenoxy)benzonitrile

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:3.91 (4H, s), 6.56 (2H, d), 7.15 (4H, d), 7.30 (1H, m), 7.46 (4H, d)

(b) The following compound was obtained in the same manner as describedin Example 11 (b).

2,6-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]benzonitrile

Starting compound: 2,6-bis[4-(hydroxyaminomethyl)phenoxy]benzonitrile

Melting point: 173°-175° C., EtOH-H₂ O

Elemental analysis (for C₂₅ H₁₇ N₅ O₈.1/2H₂ O)

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   57.26         3.46    13.35                                          found    57.20         3.47    13.13                                          ______________________________________                                    

Mass spectrometry data (m/z): 514 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.84 (4H, s), 6.66 (2H, d), 7.25 (4H, d), 7.47 (4H, d), 7.57 (1H, t)

Example 34

The following compound was obtained in the same manner as described inExample 11 (b).

2,4-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]benzonitrile

Starting compound: 2,4-bis[4-(hydroxyaminomethyl)phenoxy]benzonitrile

Melting point: 175°-177° C., EtOH-H₂ O

Mass spectrometry data (m/z): 514 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.80 (2H, s), 4.81 (2H, s), 7.53 (1H, s), 6.78 (1H, d), 7.16 (2H, d),7.20 (2H, d), 7.35 (2H, d), 7.43 (2H, d), 7.89 (1H, d)

Example 35

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

1,3-Bis[4-(hydroxyaminomethyl)phenoxy]-5-methoxybenzene

Starting compound: 1,3-bis(4-formylphenoxy)-5-methoxybenzene

Mass spectrometry data (m/z): 348 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard) δ:3.73 (3H, s), 3.96 (4H, s), 6.29 (3H, m), 7.00 (4H, d), 7.30 (4H, d)

(b) The following compound was obtained in the same manner as describedin Example 11 (b).

1,3-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]-5-methoxybenzene

Starting compound:1,3-bis[4-(hydroxyaminomethyl)phenoxy]-5-methoxybenzene

Amorphous

Mass spectrometry data (m/z): 519 ([M-H]⁻)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard) δ:3.82 (3H, s), 4.76 (4H, s), 6.18 (1H, s), 6.36 (2H, s), 6.97 (2H, d),7.29 (2H, d)

Example 36

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

1,3-Bis[4-(hydroxyaminomethyl)phenoxy]-5-fluorobenzene

Starting compound: 1,3-bis(4-formylphenoxy)-5-fluorobenzene

Mass spectrometry data (m/z): 371 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:3.86 (4H, s), 6.35 (1H, m), 6.44 (1H, d), 6.56 (1H, d), 7.03 (4H, d),7.39 (4H, d)

(b) The following compound was obtained in the same manner as describedin Example 11 (b).

1,3-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]-5-fluorobenzene

Starting compound:1,3-bis[4-(hydroxyaminomethyl)phenoxy]-5-fluorobenzene

Melting point: 182°-184° C., MeOH

Elemental analysis (for C₂₄ H₁₇ N₄ O₈ F)

    ______________________________________                                               C (%) H (%)       N (%)   F (%)                                        ______________________________________                                        calcd.   56.70   3.37        11.02 3.74                                       found    56.58   3.51        10.97 3.72                                       ______________________________________                                    

Mass spectrometry data (m/z): 507 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.79 (4H, s), 6.44 (1H, s), 6.62 (2H, d), 7.12 (4H, d), 7.39 (4H, d),12.45 (2H, brs)

Example 37

The following compound was obtained in the same manner as described inExample 11 (b).

1,3-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]-4-bromobenzene

Starting compound: 1,3-bis[4-(hydroxyaminomethyl)phenoxy]-4-bromobenzene

Amorphous

Mass spectrometry data (m/z): 568 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.76 (4H, brs), 6.74 (1H, s), 6.79 (1H, dd), 7.00 (2H, d), 7.08 (2H, d),7.36 (2H, d), 7.36 (2H, d), 7.73 (1H, d)

Example 38

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

3,5-Bis[4-(hydroxyaminomethyl)phenoxy]-N,N-dimethylaniline

Starting compound: 3,5-bis(4-formylphenoxy)-N,N-dimethylaniline

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard) δ:2.88 (6H, s), 3.90 (4H, s), 5.84 (1H, t), 6.14 (2H, d), 6.93 (4H, d),7.21 (4H, d)

(b) The following compound was obtained in the same manner as describedin Example 11 (b).

3,5-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]-N,N-dimethylaniline

Starting compound:3,5-bis[4-(hydroxyaminomethyl)phenoxy]-N,N-dimethylaniline

Amorphous

Mass spectrometry data (m/z): 534 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:2.84 (6H, s), 4.38 (4H, s), 5.81 (1H, s), 6.11 (2H, s), 6.95 (4H, d),7.28 (4H, d)

Example 39

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

2,6-Bis[4-(hydroxyaminomethyl)phenoxy]pyridine

Starting compound: 2,6-bis(4-formylphenoxy)pyridine

Mass spectrometry data (m/z): 354 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:3.86 (4H, s), 6.56 (2H, d), 7.04 (4H, d), 7.35 (4H, d), 7.82 (1H, t)

(b) The following compound was obtained in the same manner as describedin Example 11 (b).

2,6-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]pyridine

Starting compound: 2,6-bis[4-(hydroxyaminomethyl)phenoxy]pyridine

Amorphous

Mass spectrometry data (m/z): 490 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.47 (4H, s), 6.59 (2H, d), 7.08 (4H, d), 7.31 (4H, d), 7.84 (1H, t)

Example 40

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

1,3-Bis[4-(hydroxyaminomethyl)phenoxy]-4-chlorobenzene

Starting compound: 1,3-bis(4-formylphenoxy)-4-chlorobenzene

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard) δ:3.99 (4H, brs), 6.6-6.8 (2H, m), 6.93 (4H, d-like), 7.22-7.53 (5H, m)

(b) The following compound was obtained in the same manner as describedin Example 11 (b).

1,3-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]-4-chlorobenzene

Starting compound:1,3-bis[4-(hydroxyaminomethyl)phenoxy]-4-chlorobenzene

Amorphous

Mass spectrometry data (m/z): 523 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.40 (4H, s), 6.72 (1H, d), 6.78 (1H, dd), 6.95 (2H, d), 7.02 (2H, d),7.31 (2H, d), 7.56 (1H, d)

Example 41

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

1,3-Bis[2-fluoro-4-(hydroxyaminomethyl)phenoxy]benzene

Starting compound: 1,3-bis(2-fluoro-4-formylphenoxy)benzene

Mass spectrometry data (m/z): 389 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:3.87 (4H, s), 6.54 (1H, s), 6.61 (2H, d), 7.15-7.21 (4H, m), 7.33 (1H,t), 7.36 (2H, d)

(b) The following compound was obtained in the same manner as describedin Example 11 (b).

1,3-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]-2-fluorophenoxy]benzene

Starting compound:1,3-bis[2-fluoro-4-(hydroxyaminomethyl)phenoxy]benzene

Melting point: 160°-162° C., CH₃ CN-H₂ O

Elemental analysis (for C₂₄ H₁₆ N₄ F₂ O₈.1/4H₂ O)

    ______________________________________                                               C (%) H (%)       N (%)   F (%)                                        ______________________________________                                        calcd.   54.30   3.13        10.55 7.16                                       found    54.49   3.30        10.34 6.89                                       ______________________________________                                    

Mass spectrometry data (m/z): 525 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.81 (4H, s), 6.65 (1H, s), 6.70 (2H, d), 7.21-7.28 (4H, m), 7.33 (1H,t), 7.40 (2H, d)

Example 42

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

1,3-Bis[2-chloro-4-(hydroxyaminomethyl)phenoxy]benzene

Starting compound: 1,3-bis(2-chloro-4-formylphenoxy)benzene

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard) δ:3.96 (4H, s), 6.5-6.8 (3H, m), 7.00 (2H, d), 7.15-7.33 (3H, m), 7.43(2H, s)

(b) The following compound was obtained in the same manner as describedin Example 11 (b).

1,3-Bis[2-chloro-4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]benzene

Starting compound:1,3-bis[2-chloro-4-(hydroxyaminomethyl)phenoxy]benzene

Amorphous

Mass spectrometry data (m/z): 558 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.46 (4H, s), 6.58 (1H, t), 6.62 (2H, dd), 7.16 (2H, d), 7.30-7.36 (3H,m), 7.50 (1H, s)

Example 43

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

1,3-Bis[3-chloro-4-(hydroxyaminomethyl)phenoxy]benzene

Starting compound: 1,3-bis(3-chloro-4-formylphenoxy)benzene

Mass spectrometry data (m/z): 421 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard) δ:4.10 (4H, s), 6.6-7.1 (7H, m), 7.22 (1H, m), 7.34 (2H, d)

(b) The following compound was obtained in the same manner as describedin Example 11 (b).

1,3-Bis[3-chloro-4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]benzene

Starting compound:1,3-bis[3-chloro-4-(hydroxyaminomethyl)phenoxy]benzene

Amorphous

Mass spectrometry data (m/z): 558 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.49 (4H, d), 6.80 (1H, s), 6.83 (2H, d), 7.06 (2H, dd), 7.16 (2H, d),7.42 (1H, t), 7.48 (2H, d)

Example 44

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

1,3-Bis(4-hydroxyaminomethylphenoxy)-5-methylbenzene

Starting compound: 1,3-bis(4-formylphenoxy)-5-methylbenzene

Mass spectrometry data (m/z): 366 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)##STR58##

(b) The following compound was obtained in the same manner as describedin Example 10 (b).

1,3-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]-5-methylbenzene

Starting compound: 1,3-bis(4-hydroxyaminomethylphenoxy)-5-methylbenzene

Elemental analysis (for C₂₅ H₂₀ N₄ O₈)

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   59.52         4.00    11.11                                          found    59.42         4.00    11.06                                          ______________________________________                                    

Mass spectrometry data (m/z): 503 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR59##

Example 45

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

1,3-Bis(4-hydroxyaminomethylphenoxy)-4,6-dichlorobenzene

Starting compound: 1,3-bis(4-formylphenoxy)-4,6-dichlorobenzene

Mass spectrometry data (m/z): 421 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR60##

(b) The following compound was obtained in the same manner as describedin Example 10 (b).

1,3-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]-4,6-dichlorobenzene

Starting compound:1,3-bis(4-hydroxyaminomethylphenoxy)-4,6-dichlorobenzene

Melting point: 217°-8° C.

Mass spectrometry data (m/z): 557 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR61##

Example 46

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

1,3-Bis(4-hydroxyaminomethylphenoxy)-4-ethylbenzene

Starting compound: 1,3-bis(4-formylphenoxy)-4-ethylbenzene

Mass spectrometry data (m/z): 381 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard) δ:1.19 (3H, t, --CH₂ CH₃), 2.62 (2H, q, --CH₂ CH₃), ##STR62## 6.25-7.50(11H, m, phenyl)

(b) The following compound was obtained in the same manner as describedin Example 10 (b).

1,3-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]-4-ethylbenzene

Starting compound: 1,3-bis(4-hydroxyaminomethylphenoxy)-4-ethylbenzene

Mass spectrometry data (m/z): 517 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:1.13 (3H, t, --CH₂ CH₃), 2.54 (2H, q, --CH₂ CH₃), ##STR63## 6.50-7.40(1H, m, phenyl)

Example 47

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

3,5-Bis(4-hydroxyaminomethylphenoxy)benzamide

Starting compound: 3,5-bis(4-formylphenoxy)benzamide

Mass spectrometry data (m/z): 396 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR64##

(b) The following compound was obtained in the same manner as describedin Example 10 (b).

3,5-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]benzamide

Starting compound: 3,5-bis(4-hydroxyaminomethylphenoxy)benzamide

Mass spectrometry data (m/z): 532 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR65##

Example 48

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

1,3-Bis[4-(N-hydroxyaminomethyl)-2-trifluoromethylphenoxy]benzene

Starting compound: 1,3-bis(4-formyl-2-trifluoromethylphenoxy)benzene

Mass spectrometry data (m/z): 489 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard) δ:4.02 (4H, s), 6.50 (1H, t), 6.80 (2H, d), 6.96 (2H, d), 7.31 (1H, t),7.45 (2H, d), 7.63 (2H, d)

(b) The following compound was obtained in the same manner as describedin Example 11 (b).

1,3-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]-2-trifluoromethylphenoxy]benzene

Starting compound:1,3-bis[4-(N-hydroxyaminomethyl)-2-trifluoromethylphenoxy]benzene

Mass spectrometry data (m/z): 625 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.88 (4H, s), 6.83 (1H, t), 6.88 (2H, d), 7.18 (2H, d), 7.47 (1H, t),7.65 (2H, d), 7.76 (2H, s), 12.50 (2H, brs)

Example 49

(a) Using a hydroxylamine compound obtained in the same manner asdescribed in Example 10 (a), the following compound was obtained inaccordance with the procedure of Example 11 (b).

1,3-Bis[2,6-difluoro-4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]benzene

Starting compound: 1,3-bis(2,6-difluoro-4-formylphenoxy)benzene

Melting point: >300° C. (decomposition)

Mass spectrometry data (m/z): 561 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.46 (4H, s), 6.60 (2H, dd), 6.67 (1H, t), 7.23 (4H, d), 7.31 (1H, t)

Example 50

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

1,3-Bis[4-(N-hydroxyaminomethyl)-3-trifluoromethylphenoxy]benzene

Starting compound: 1,3-bis(4-formyl-3-trifluoromethylphenoxy)benzene

Mass spectrometry data (m/z): 489 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard) δ:4.17 (4H, s), 6.55 (1H, d), 6.80 (2H, d), 7.14 (2H, d), 7.31-7.35 (3H,m), 7.55 (2H, d)

(b) The following compound was obtained in the same manner as describedin Example 11 (b).

1,3-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]-3-trifluoromethylphenoxy]benzene

Starting compound:1,3-bis[4-(N-hydroxyaminomethyl)-3-trifluoromethylphenoxy]benzene

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.61 (4H, s), 6.87-6.90 (3H, m), 7.36-7.39 (4H, m), 7.46 (1H, t), 7.69(2H, d)

Example 51

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

3-[4-(N-Hydroxyaminomethyl)phenoxy]-N-[4-(N-hydroxyaminomethyl)phenyl]-N-methylaniline

Starting compound:3-(4-formylphenoxy)-4-(4-formylphenyl)-N-methylaniline

Mass spectrometry data (m/z): 366 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard) δ:3.26 (3H, s), 3.95 (4H, s), 6.43 (1H, s), 6.53 (1H, d), 6.65 (1H, d),6.95 (2H, d), 7.02 (2H, d), 7.15-7.30 (5H, m)

(b) The following compound was obtained in the same manner as describedin Example 11 (b).

3-[4-[(3,5-Dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]-N-[4-(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenyl-N-methylaniline

Starting compound:3-[4-(N-hydroxyaminomethyl)phenoxy]-N-[4-(N-hydroxyaminomethyl)phenyl]-N-methylaniline

Mass spectrometry data (m/z): 502 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:3.25 (3H, s), 4.70 (2H, s), 4.73 (2H, s), 6.51 (1H, d), 6.62 (1H, t),6.74 (1H, d), 7.01 (2H, d), 7.09 (2H, d), 7.23-7.27 (3H, m), 7.33 (2H,d)

Example 52

(a) The following compound was obtained in the same manner as describedin Example 10 (a).

1,3-Bis[4-(N-hydroxyaminomethyl)phenoxy]benzene

Starting compound: 1,3-bis(4-formylphenoxy)benzene

Melting point: 110°-114° C.

Mass spectrometry data (m/z): 353 ([M+1]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:3.84 (4H, s), 5.98 (2H, s), 6.55 (1H, t, J=2.44 Hz), 6.69 (2H, dd,J=2.44 and 8.32 Hz), 6.99 (4H, d, J=8.28 Hz), 7.24 (2H, s), 7.34 (1H, d,J=8.32 Hz), 7.35 (4H, d, J=8.28 Hz)

(b) 1,3-Bis[4-(N-hydroxyaminomethyl)phenoxy]benzene (0.704 g) wasdissolved in 21 ml of tetrahydrofuran to which, with ice-cooling and inan atmosphere of argon, was subsequently added dropwise 0.354 ml ofchlorocarbonyl isocyanate. After 10 minutes of stirring at the sametemperature, the stirring was continued for 2 hours at room temperature.The solvent was evaporated under a reduced pressure, and the resultingresidue was subjected to silica gel column chromatography to obtain 0.44g of1,3-bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]benzenefrom fractions of chloroform-methanol (30:1) elution.

The physicochemical properties showed that this compound is the samecompound as the product of Example 55 b.

Example 53

1,3-bis[4-(N-hydroxyaminomethyl)phenoxy]benzene (1.76 g) was dissolvedin 35 ml of tetrahydrofuran to which, with ice-cooling and in anatmosphere of argon, was subsequently added dropwise 1.65 g ofn-butoxycarbonyl isocyanate. After 30 minutes of stirring at the sametemperature, 1N sodium hydroxide aqueous solution was added dropwisethereto and the stirring was continued for 30 minutes at roomtemperature. After adding 1N hydrochloric acid, the solvent wasevaporated, and the resulting residue was subjected to silica gel columnchromatography to obtain 1.0 g of1,3-bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]benzenefrom fractions of chloroform-methanol (30:1) elution.

The physicochemical properties showed that this compound is the samecompound as the product of Example 55 b.

Example 54

Phenol (3.76 g) was dissolved in 15 ml of tetrahydrofuran and 1.24 g ofethoxycarbonyl isocyanate was added dropwise in an atmosphere of argonat room temperature. After 3 hours of stirring at the same temperature,1.41 g of 1,3-bis[4-(N-hydroxyaminomethyl)phenoxy]benzene was added andthe stirring was continued for 1 hour. After addition of 3 drops oftriethylamine and subsequent 16 hours of stirring at 60° C., 1N sodiumhydroxide aqueous solution was added dropwise to the reaction mixturewith ice-cooling, followed by 1 hour of stirring at room temperature.This was mixed with 1N hydrochloric acid, the solvent was evaporated andthen water was added to the resulting residue to obtain 0.8 g of crudecrystals. They were further washed with diethyl ether and ethanol toobtain 0.4 g of1,3-bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]benzene.

The physicochemical properties showed that this compound is the samecompound with the product of Example 55 b.

Example 55

(a) 1,3-Bis[4-(hydroxyaminomethyl)phenoxy]benzene (1.06 g) was dissolvedin 10 ml of tetrahydrofuran to which, with ice-cooling and in anatmosphere of argon, was subsequently added dropwise 0.68 ml ofethoxycarbonyl isocyanate. After 2 hours and 30 minutes of stirring atthe room temperature, the thus formed crystals were collected byfiltration and washed with diethyl ether and ethanol to obtain 1.09 g of1,3-bis[4-[1-(3-ethoxycarbonyl-1-hydroxyurenylene)methyl]phenoxy]benzene.

Melting point: 145°-148° C.

Mass spectrometry data (m/z): 583 ([M+H]⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR66##

(b)1,3-Bis[4-[1-(3-ethoxycarbonyl-1-hydroxyurenylene)methyl]phenoxy]benzene(0.85 g) was dispersed in 8.5 ml of tetrahydrofuran to which, withice-cooling, was subsequently added dropwise 1N sodium hydroxide aqueoussolution, followed by 30 minutes of stirring at room temperature. Afteradding 1N hydrochloric acid, the solvent was evaporated under a reducedpressure, and water was added to the resulting residue. The thus formedcrystals were collected by filtration and recrystallized from aceticacid to obtain 0.35 g of1,3-bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]benzene.

Melting point: 182°-184° C.

Elemental analysis (for C₂₄ H₁₈ N₄ O₈)

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   58.78         3.70    11.42                                          found    58.77         3.83    11.37                                          ______________________________________                                    

Mass spectrometry data (m/z): 489 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)##STR67##

Example 56

(a) The following compound was obtained in the same manner as describedin Reference Example 22 (b).

Bis(4-formylphenyl)methylamine

Mass spectrometry data (m/z): 240 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard) δ:3.49 (3H, s), 7.19 (4H, d), 7.83 (4H, d), 9.90 (2H, s)

(b) The following compound was obtained in the same manner as describedin Example 10 (a).

Bis(4-hydroxyaminomethylphenyl)methylamine

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard) δ:3.26 (3H, s), 3.92 (4H, s), 5.40 (2H, brs), 6.94 (4H, d), 7.20 (4H, d)

(c) The following compound was obtained in the same manner as describedin Reference Example 11 (b).

Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenyl]methylamine

Mass spectrometry data (m/z): 410 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:3.27 (3H, s), 4.72 (4H, s), 7.02 (4H, d), 7.25 (4H, d), 12.42 (2H, brs)

Elemental analysis (for C₁₉ H₁₇ N₅ O₆)

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        calcd.   55.47         4.17    17.02                                          found    55.20         4.08    16.85                                          ______________________________________                                    

Example 57

(a) The following compound was obtained in the same manner as describedin Reference Example 22 (b).

Bis(4-formylphenyl) sulfide

Mass spectrometry data (m/z): 243 ([M+H]⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard) δ:7.48 (4H, d), 7.85 (4H, d), 10.00 (2H, s)

(b) The following compound was obtained in the same manner as describedin Example 10 (a).

Bis(4-hydroxyaminomethylphenyl) sulfide

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:3.84 (4H, s), 6.01 (2H, s), 7.20-7.40 (8H, m)

(c) The following compound was obtained in the same manner as describedin Reference Example 11 (b).

Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenyl]sulfide

Mass spectrometry data (m/z): 413 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.79 (4H, s), 7.36 (8H, s), 12.46 (2H, brs)

Elemental analysis (for C₁₈ H₁₄ N₄ O₆ S)

    ______________________________________                                               C (%) H (%)       N (%)   S (%)                                        ______________________________________                                        calcd.   52.17   3.41        13.52 7.74                                       found    52.17   3.47        13.22 7.73                                       ______________________________________                                    

Example 58

At room temperature, 1.76 g of metachloroperbenzoic acid was added to amixture of 910 mg ofbis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenyl]thioether and 5ml of dichloromethane and the mixture was stirred for 15 hours. The thusformed crystals were collected by filtration, washed withdichloromethane and then dried to obtain 730 mg ofbis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenyl]sulfone.

Mass spectrometry data (m/z): 445 ([M-H]⁻)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard) δ:4.90 (4H, s), 7.60 (4H, d), 8.00 (4H, d), 12.50 (2H, brs)

Structures of the compounds obtained in Examples are shown in Table 2.

                                      TABLE 2                                     __________________________________________________________________________     ##STR68##                                                                    Ex. No.                                                                           ##STR69##                                                                             L                                                                                               ##STR70##                                       __________________________________________________________________________        ##STR71##                                                                             O                                                                                               ##STR72##                                       2  "        CH.sub.2         "                                                3  "                                                                                       ##STR73##       "                                                4  "                                                                                       ##STR74##       "                                                5  "        O(CH.sub.2).sub.5O                                                                             "                                                6  "                                                                                       ##STR75##       "                                                7  "                                                                                       ##STR76##       "                                                8  "                                                                                       ##STR77##       "                                                9                                                                                 ##STR78##                                                                              ##STR79##                                                                                      ##STR80##                                       10 "                                                                                       ##STR81##       "                                                11 "        O(CH.sub.2).sub.9O                                                                             "                                                12 "        O(CH.sub.2).sub.4O                                                                             "                                                13 "        O(CH.sub.2).sub.6O                                                                             "                                                14 "                                                                                       ##STR82##       "                                                15 "        O(CH.sub.2).sub.7O                                                                             "                                                16 "                                                                                       ##STR83##       "                                                17 "                                                                                       ##STR84##       "                                                18 "                                                                                       ##STR85##       "                                                19                                                                                ##STR86##                                                                              ##STR87##                                                                                      ##STR88##                                       20 "        O(CH.sub.2).sub.8O                                                                             "                                                21 "        O(CH.sub.2).sub.2O(CH.sub.2).sub.2O                                                            "                                                22 "        O(CH.sub.2).sub.2O                                                                             "                                                23 "        O(CH.sub.2).sub.3O                                                                             "                                                24 "        O(CH.sub.2).sub.10O                                                                            "                                                25 "        O(CH.sub.2).sub.11O                                                                            "                                                26 "        O(CH.sub.2).sub.12O                                                                            "                                                27 "                                                                                       ##STR89##       "                                                28 "                                                                                       ##STR90##       "                                                29                                                                                ##STR91##                                                                              ##STR92##                                                                                      ##STR93##                                       30 "                                                                                       ##STR94##       "                                                31 "                                                                                       ##STR95##       "                                                32 "                                                                                       ##STR96##       "                                                33 "                                                                                       ##STR97##       "                                                34 "                                                                                       ##STR98##       "                                                35 "                                                                                       ##STR99##       "                                                36 "                                                                                       ##STR100##      "                                                37 "                                                                                       ##STR101##      "                                                38 "                                                                                       ##STR102##      "                                                39                                                                                ##STR103##                                                                             ##STR104##                                                                                     ##STR105##                                      40 "                                                                                       ##STR106##      "                                                41                                                                                ##STR107##                                                                             ##STR108##                                                                                     ##STR109##                                      42                                                                                ##STR110##                                                                            "                                                                                               ##STR111##                                      43                                                                                ##STR112##                                                                            "                                                                                               ##STR113##                                      44                                                                                ##STR114##                                                                             ##STR115##                                                                                     ##STR116##                                      45 "                                                                                       ##STR117##      "                                                46 "                                                                                       ##STR118##      "                                                47 "                                                                                       ##STR119##      "                                                48                                                                                ##STR120##                                                                             ##STR121##                                                                                     ##STR122##                                      49                                                                                ##STR123##                                                                            "                                                                                               ##STR124##                                      50                                                                                ##STR125##                                                                            "                                                                                               ##STR126##                                      51                                                                                ##STR127##                                                                             ##STR128##                                                                                     ##STR129##                                      52 "                                                                                       ##STR130##      "                                                53 "        "                "                                                54 "        "                "                                                55 "        "                "                                                56 "                                                                                       ##STR131##      "                                                57 "        S                "                                                58 "        SO.sub.2         "                                                __________________________________________________________________________

We claim:
 1. A bisoxadiazolidine dione derivative represented by thefollowing general formula (I) ##STR132## symbols in the formularepresent the following meanings; ##STR133## the same or different fromeach other and each represents a phenylene group which may besubstituted,L: (1) an oxygen atom, (2) a group represented by theformula ##STR134## (3) a group represented by the formula --S(O)_(n) --,(4) a group represented by the formula --CO--, (5) a group representedby the formula ##STR135## (6) an alkylene group or an alkenylene groupwhich may respectively be interrupted with an oxygen atom and/or asulfur atom and which may each be substituted, or (7) a grouprepresented by a formula ##STR136## R¹ : a hydrogen atom or a loweralkyl group, n: 0, 1 or 2, R² : a hydrogen atom or a lower alkyl group,L¹ and L² : the same or different from each other and each represents(1)an oxygen atom, (2) a group represented by the formula ##STR137## R¹ isas defined in the foregoing, (3) a group represented by the formula--S(O)_(n) --, n is as defined in the foregoing, (4) a group representedby the formula --CO--, (5) a group represented by the formula ##STR138##R² is as defined in the foregoing, or (6) an alkylene group or analkenylene group which may respectively be interrupted with an oxygenatom and/or a sulfur atom and which may each be substituted, and##STR139## a cycloalkanediyl group, an arylene group or a pyridinediylgroup, which may respectively be substituted, or a pharmaceuticallyacceptable salt thereof.
 2. The compound according to claim 1, whereinsubstituents on ##STR140## when present, are one or more substituentsselected from the group consisting of a halogen atom, a lower alkylgroup, a halo-lower alkyl group, a lower alkoxy group, a cyano group, anitro group, an amino group, a lower alkyl-substituted amino group, acarbamoyl group and a lower alkyl-substituted carbamoyl group, and thesubstituent on L, L¹ and L², when present, is a halogen atom.
 3. Thecompound according to claim 2, wherein ##STR141## may be the same ordifferent from each other and each represents a phenylene group whichmay be substituted with one or more substituents selected from the groupconsisting of a halogen atom, a lower alkyl group and a halo-lower alkylgroup, and L is (1) an alkylene group or an alkenylene group which mayrespectively be interrupted with an oxygen atom and/or a sulfur atom andwhich may each be substituted with one or more halogen atoms, or (2) agroup represented by ##STR142## wherein L¹ and L² may be the same ordifferent from each other and each represents an alkylene group or analkenylene group which may respectively be interrupted with an oxygenatom and/or a sulfur atom and may each be substituted with one or morehalogen atoms and ##STR143## is a cycloalkanediyl group, an arylenegroup or a pyridinediyl group which may each be substituted with one ormore substituents selected from the group consisting of a halogen atom,a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, acyano group, a nitro group, an amino group, a lower alkyl-substitutedamino group, a carbamoyl group and a lower alkyl-substituted carbamoylgroup. 4.1,3-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]benzene ora pharmaceutically acceptable salt thereof. 5.1,4-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]-2-buteneor a pharmaceutically acceptable salt thereof. 6.1,9-Bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]nonane ora pharmaceutically acceptable salt thereof.
 7. A pharmaceuticalcomposition which comprises a bisoxadiazolidine dione derivativerepresented by the following general formula (I) or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier##STR144## symbols in the formula represent the following meanings;##STR145## the same or different from each other and each represents aphenylene group which may be substituted,L: (1) an oxygen atom, (2) agroup represented by the formula ##STR146## (3) a group represented bythe formula --S(O)_(n) --, (4) a group represented by the formula--CO--, (5) a group represented by the formula ##STR147## (6) analkylene group or an alkenylene group which may respectively beinterrupted with an oxygen atom and/or a sulfur atom and which may eachbe substituted, or (7) a group represented by a formula ##STR148## R¹ :a hydrogen atom or a lower alkyl group, n: 0, 1 or 2, R² : a hydrogenatom or a lower alkyl group, L¹ and L² : the same or different from eachother and each represents(1) an oxygen atom, (2) a group represented bythe formula ##STR149## R¹ is as defined in the foregoing, (3) a grouprepresented by the formula --S(O)_(n) --, n is as defined in theforegoing, (4) a group represented by the formula --CO--, (5) a grouprepresented by the formula ##STR150## R² is as defined in theforegoing), or (6) an alkylene group or an alkenylene group which mayrespectively be interrupted with an oxygen atom and/or a sulfur atom andwhich may each be substituted, and ##STR151## a cycloalkanediyl group,an arylene group or a pyridinediyl group, which may respectively besubstituted.
 8. The pharmaceutical composition according to claim 7,having insulin sensitivity-increasing activity.
 9. The pharmaceuticalcomposition according to claim 7, having hypoglycemic activity.
 10. Thepharmaceutical composition according to claim 7, useful in the treatmentof diabetes mellitus and/or the prevention and/or treatment of diabeticcomplications.